WO2024104968A1 - Pyrazolopyrrolopyridazines and their uses as pdgfr inhibitors - Google Patents

Pyrazolopyrrolopyridazines and their uses as pdgfr inhibitors Download PDF

Info

Publication number
WO2024104968A1
WO2024104968A1 PCT/EP2023/081630 EP2023081630W WO2024104968A1 WO 2024104968 A1 WO2024104968 A1 WO 2024104968A1 EP 2023081630 W EP2023081630 W EP 2023081630W WO 2024104968 A1 WO2024104968 A1 WO 2024104968A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
amino
pyrrolo
pyridazin
pyrazolo
Prior art date
Application number
PCT/EP2023/081630
Other languages
French (fr)
Inventor
Tianbao Lu
Zhijie Liu
Original Assignee
Actelion Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of WO2024104968A1 publication Critical patent/WO2024104968A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • Protein kinases play a critical role in the control cell growth, proliferation, differentiation, metabolism, apoptosis, cell mobility, transcription, translation and other signaling processes.
  • the overexpression or inappropriate expression of protein kinases plays a significant role in the development of many diseases and disorders including central nervous system disorders, inflammatory disorders, metabolic disorders, autoimmune diseases, cardiovascular diseases, fibrotic diseases, transplantation rejection, cancer and infectious diseases.
  • Growth factors are important regulators of human homeostasis involved in maintaining a delicate balance between cell growth, differentiation, and proliferation. Consequently, dysregulation of GF signaling are implicated in many diseases including oncology, immunology, fibroproliferative, cardiovascular, vascular disorders and pulmonary hypertension.
  • GF bind to several different receptors that amplify the signal through activation of the specific receptor through phosphorylation, leading to confirmation changes increasing the affinity for ATP and the phosphorylation of downstream proteins leading to activation of several signaling cascades. Therefore, small changes in GF or the cognate receptors can significantly alter the local signaling and have dramatic effects on initiation and progression of many diseases.
  • Platelet-derived growth factor (PDGF) is one of many GFs that regulate cell growth and division.
  • PDGFR ⁇ and PDGFR ⁇ which (ACT6051WOPCT1) can form three different dimeric receptors – ⁇ , ⁇ and ⁇ . These receptors can interact with the different dimeric PDGF ligands (PDGF-AA, PDGF-BB, PDGF-CC, PDGF-DD and PDGF-AB) with different specificities and efficacies.
  • the receptors are activated by ligand- induced dimerization, leading to autophosphorylation on specific tyrosine residues.
  • PDGFR phosphorylation recruits signaling proteins containing Tyr(P)-binding domains.
  • MAP Ras-mitogen activated protein
  • PI3kinase-Akt the PI3kinase-Akt pathway
  • PLC-y1 the PI3kinase-Akt pathway
  • PDGFR Platelet-derived growth factor
  • PDGFR ⁇ and PDGFR ⁇ play important roles in tumorigenesis, tumor progression, and the regulation of stromal cell function. Constitutive activation of PDGFR signaling, gene rearrangement, and activating mutations of PDGFR have been identified in various types of human tumors and malignancies. [0006] PDGFR signaling is implicated in the development and progression of pulmonary hypertension. PDGFs are expressed in ECs, SMCs and macrophages and are strong mitogens and chemokines. Increased signaling through PDGFR ⁇ leads to smooth muscle cell proliferation which contributes to the development of vascular remodeling.
  • PDGF and PDGF receptors are upregulated in human and animals with pulmonary hypertension.
  • efficacy in preventing and reversing vascular remodeling in experimentally induced pulmonary hypertension was demonstrated through non-selective inhibition of PDGF receptors.
  • imatinib also known as Gleevec
  • dasatinib a receptor tyrosine kinases inhibitor
  • the present disclosure provides PDGFR inhibitors.
  • A is an optionally substituted phenyl ring or an optionally substituted pyridinyl ring;
  • R 1 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 5 cycloalkyl;
  • R 2 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted C 1 -C 6 -alkyl-cycloalkyl, optionally substituted C 1 -C 6 -alkyl, or optionally substituted heterocycloalkyl;
  • n is 1, 2, or 3;
  • R 3 and R 4 are each independently optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted C 1 -C 6 -alkyl-cycloalkyl, optionally substituted C 1 -C 6 -alkyl, or optionally substituted heterocycloalkyl
  • compositions comprising such compounds, and methods of using such compounds in treating conditions in which PDGFR signaling is implicated are also provided.
  • compounds of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in which PDGFR signaling is implicated in a subject in need thereof are also provided.
  • the disclosure also provides the use of a compounds of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder in which PDGFR signaling is implicated in a subject in need thereof.
  • Deuterated small molecules contemplated are those in which one or more of the hydrogen atoms contained in the drug molecule have been replaced by deuterium. It is understood by those of ordinary skill that molecules which are described herein are stable compounds as generally described hereunder.
  • “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, e.g., in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- (ACT6051WOPCT1) hydroxyethanesulfonic acid, benzenesulfonic acid,
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • a “pharmaceutically acceptable excipient” refers to a substance that is non- toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith.
  • a “solvate” refers to a physical association of a compound of formula (I) with one or more solvent molecules.
  • alkyl when used alone or as part of a substituent group, refers to a straight- or branched-chain hydrocarbon group having from 1 to 12 carbon atoms (“C 1 - C 12 ”), preferably 1 to 6 carbons atoms (“C 1 -C 6 ”), in the group.
  • alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like.
  • the alkyl group is a C 1 -C 6 alkyl; in some embodiments, it is a C 1 -C 4 alkyl.
  • a range of carbon atoms is used herein, for example, C 1 -C 6 , all ranges, as well as individual numbers of carbon atoms are encompassed.
  • C 1 -C 3 includes C 1 -C 3 , C 1 -C 2 , C 2 -C 3 , C 1 , C 2 , and C 3 .
  • cycloalkyl when used alone or as part of a substituent group refers to cyclic-containing, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms (“C 3- C 10 ”), preferably from 3 to 6 carbon atoms (“C 3- C 6 ”).
  • cycloalkyl (ACT6051WOPCT1) groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.1.0]heptanyl, spiro[3.3]heptanyl, and spiro[3.4]octanyl.
  • fluoroalkyl when used alone or as part of a substituent group refers to an alkyl group wherein one or more of the hydrogen atoms has been replaced with one or more fluorine atoms.
  • fluoroalkyl groups examples include -CF 3 , CHF 2 , -CH 2 F and the like.
  • the term “heterocycloalkyl” when used alone or as part of a substituent group refers to any three to twelve-membered monocyclic, saturated or partially unsaturated ring containing at least one heteroatom that is O, N or S.
  • the heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
  • heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.
  • bridged heterocycloalkyl ring refers to any 5 to 12 membered heterocycloalkyl ring system that contains at least one bridged ring.
  • bridged heterocycloalkyl rings include azabicyclo[3.1.1]heptane, azabicyclo[3.1.1]heptane, azabicyclo[2.2.2]octane, azabicyclo[2.2.1]heptane, azabicyclo[2.1.1]hexane, azabicyclo[1.1.1]pentane, azabicyclo[1.1.1]pentane, 6-oxa-azabicyclo[3.1.1]heptane, 6- diazabicyclo[3.1.1]heptane, 3-thia-azabicyclo[3.1.1]heptane, and the like.
  • fused heterocycloalkyl ring system refers to a heterocycloalkyl ring to which another ring is fused.
  • the other ring that is fused to the heterocycle ring may be another heterocycloalkyl ring, a cycloalkyl ring, an aryl ring, or a heteroaryl ring.
  • the fused heterocycloalkyl ring system is a 4 to 12 membered fused heterocycloalkyl ring system.
  • spiroheterocycloalkyl ring system refers to a heterocycloalkyl ring that is substituted with a spirocyclic ring.
  • the spirocyclic ring can be a cycloalkyl ring of a heterocycloalkyl ring.
  • the spiroheterocycloalkyl ring system is a 5-12-membered spiroheterocycloalkyl ring system.
  • halo or “halogen”, by itself or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom.
  • aryl when used alone or as part of a substituent group also refers to a mono- or bicyclic- aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more of the carbon atoms in the ring is optionally substituted.
  • aryl also includes a mono- or bicyclic- aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein two adjacent carbon atoms in the ring are optionally substituted such that said two adjacent carbon atoms and their respective substituents form a cycloalkyl or heterocycloalkyl ring.
  • aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3,4-tetrahydronaphthyl, and the like.
  • heteroaryl when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic ring structure including carbon atoms as well as up to four heteroatoms that are each independently nitrogen, oxygen, or sulfur. Heteroaryl rings can include a total of 5, 6, 9, or 10 ring atoms. The heteroaryl moiety can be unsubstituted, or one or more of the carbon atoms in the ring can be substituted.
  • heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3- b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole.
  • a substituent may be optionally substituted with one or more of: halo (i.e., -F, -Cl, -Br, -I), cyano, -OH, -C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1- C 6 haloalkyl, -C 1 - C 6 alkoxy, -C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, -NH 2 , -NH(C 1 -C 6 alkyl), - N(C 1 -C -6 al
  • a substituent may be optionally substituted with one or more of: halo (i.e., -F, -Cl, -Br, -I), cyano, -C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 (ACT6051WOPCT1) alkynyl, C 1 -C 6 haloalkyl, -C 1 -C 6 alkoxy, -C 1 -C 6 alkyl-O-C 1 -C 6 alkyl, -C 1 -C 6 haloalkoxy, C 1 - C 6 alkylthio, C 1 -C 6 alkylamino, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C- 6 alkyl) 2 , -NH(C 1 -C 6 alkoxy), -C(O
  • each of the above optional substituents are themselves optionally substituted by one or two groups.
  • a substituent may be optionally substituted with one or more of: halo (i.e., -F, -Cl, -Br, -I), cyano, -OH, -C 1 -C 6 alkyl, -CH 2 CH 2 OH, -CH 2 CH 2 F, - OCH 2 CH 2 F, -CH 2 CH 2 CH(OH)CH 2 (OH), -CH 2 CH(OH)CH 2 (OH), -CH 2 CH(OH)CH 3 , - CH 2 OH, -C (CH 3 ) 2 CH 2 (OH), -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 -(C 3 -C 6 cycloalkyl), -C 3 - C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C
  • each of the above optional substituents are themselves optionally substituted by one or two groups.
  • alkenyl refers to a straight- or branched-chain group having from 2 to 12 carbon atoms (“C 2- C 12 ”), preferably 2 to 4 carbons atoms (“C 2 - C 4 ”), in the group, wherein the group includes at least one carbon-carbon double bond.
  • alkynyl refers to a straight- or branched-chain group having from 1 to 12 carbon atoms (“C 1- C 12 ”), preferably 1 to 4 carbons atoms (“C 2 - C 4 ”), in the group, and wherein the group includes at least one carbon-carbon triple bond.
  • alkynyl groups include ethynyl (-C ⁇ CH; C 2 alkynyl); propargyl (-CH 2 -C ⁇ CH; C 3 alkynyl), propynyl (-C ⁇ CCH 3 ; C 3 alkynyl); butynyl (-C ⁇ CCH 2 CH 3 ; C 4 alkynyl), pentynyl (-C ⁇ CCH 2 CH 2 CH 3 ; C 5 alkynyl), and the like.
  • alkoxy refers to an oxygen radical attached to an alkyl group by a single bond.
  • alkoxy groups examples include methoxy (-OCH 3 ), ethoxy (-OCH 2 CH 3 ), isopropoxy (-OCH(CH 3 ) 2 ) and the like.
  • haloalkoxy refers to an oxygen radical attached to a haloalkyl group by a single bond. Examples of haloalkoxy groups include -OCF 3 , - OCH 2 CF 3 , -OCH(CF 3 ) 2 , and the like.
  • haloalkyl refers to an alkyl group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms.
  • haloalkoxy refers to an alkoxy group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space, e.g., enantiomers, diastereomers or tautomers.
  • patient or “subject” is used throughout the specification to describe an animal, preferably a human or a domesticated animal, to whom treatment, including prophylactic treatment, with the compositions according to the present disclosure is provided.
  • patient refers to that specific animal, including a domesticated animal such as a dog or cat or a farm animal such as a horse, cow, sheep, etc.
  • patient refers to a human patient unless otherwise stated or implied from the context of the use of the term.
  • effective is used to describe an amount of a compound, composition or component which, when used within the context of its intended use, effects an (ACT6051WOPCT1) intended result.
  • effective subsumes all other effective amount or effective concentration terms, which are otherwise described or used in the present application.
  • Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (e.g., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.
  • references herein to methods of treatment using one or more compounds or formulations thereof should also be interpreted as references to: • one or more compounds or formulations thereof (e.g. a compound of formula (I)) for use in methods of treatment; and/or • the use of one or more compounds or formulations thereof (e.g. a compound of formula (I)) in the manufacture of a medicament for treating a pathological condition.
  • the disclosure is directed to a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted phenyl ring or an optionally substituted pyridinyl ring; R 1 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 5 cycloalkyl; (ACT6051WOPCT1) R 2 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted C 1 -C 6 -alkyl-cycloalkyl, optionally substituted C 1 -C 6 -alkyl, or optionally substituted heterocycloalkyl; n is 1, 2, or 3; R 3 and R 4 are each independently optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted spirocycloalkyl, or optionally substituted heterocycl
  • A is an optionally substituted phenyl ring.
  • A is an optionally substituted pyridinyl ring.
  • R 1 in the compounds of formula (I) is optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 5 cycloalkyl.
  • (ACT6051WOPCT1) [0051]
  • R 1 is optionally substituted C 1 -C 6 alkyl, such as, for example, optionally substituted: C 6 alkyl, C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl, C 1 alkyl, methyl, ethyl, and the like.
  • the optionally substituted C 1 -C 6 alkyl is substituted C 1 -C 6 alkyl. In other embodiments, the optionally substituted C 1 -C 6 alkyl is unsubstituted C 1 - C 6 alkyl. [0052] In some embodiments, R 1 is methyl. [0053] In other embodiments, R 1 is optionally substituted C 3 -C 5 cycloalkyl, such as, for example, optionally substituted: C 5 cycloalkyl, C 4 cycloalkyl, C 3 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • R 2 in the compounds of formula (I) is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted C 1 -C 6 -alkyl-cycloalkyl, optionally substituted C 1 -C 6 -alkyl, or optionally substituted heterocycloalkyl.
  • R 2 is optionally substituted aryl.
  • R 2 is optionally substituted heteroaryl.
  • R 2 is unsubstituted heteroaryl, such as, for example, pyrazinyl, pyrimidinyl, oxazolyl, or pyridinyl.
  • R 2 is pyrazinyl.
  • R 2 is pyrimidin-5-yl or pyrimidin-4-yl.
  • R 2 is oxazol-5-yl.
  • R 2 is pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl.
  • R 2 is substituted heteroaryl, such as, for example, substituted pyrazolyl, substituted imidazolyl, substituted triazolyl, substituted furanyl, substituted thiophenyl, substituted pyrimidinyl, or substituted pyridinyl. [0063] In some embodiments, R 2 is substituted pyrazolyl.
  • R 2 is 1-methylpyrazol-5-yl, 1-methylpyrazol-4-yl, 1,3-dimethylpyrazol-4-yl, 1-cyclopropylpyrazol-4-yl, 1-(2-methoxyethyl)-pyrazol-4-yl, 1-(2- hydroxyethyl)-pyrazol-4-yl, 5-(hydroxymethyl)-1-methylpyrazol-3-yl, 1-(2,3- dihydroxypropan-1-yl)-pyrazol-4-yl, 1-(acetamid-2-yl)-pyrazol-4-yl, or 1-(oxetan-3-yl)- pyrazol-4-yl.
  • R 2 is 1-methylpyrazol-5-yl. [0066] In some embodiments, R 2 is 1-methylpyrazol-4-yl. (ACT6051WOPCT1) [0067] In some embodiments, R 2 is 1,3-dimethylpyrazol-4-yl. [0068] In some embodiments, R 2 is 1-cyclopropylpyrazol-4-yl. [0069] In some embodiments, R 2 is 1-(2-methoxyethyl)-pyrazol-4-yl. [0070] In some embodiments, R 2 is 1-(2-hydroxyethyl)-pyrazol-4-yl.
  • R 2 is 5-(hydroxymethyl)-1-methylpyrazol-3-yl.
  • R 2 is 1-(2,3-dihydroxypropan-1-yl)-pyrazol-4-yl.
  • R 2 is 1-(acetamid-2-yl)-pyrazol-4-yl.
  • R 2 is 1-(oxetan-3-yl)-pyrazol-4-yl.
  • R 2 is substituted imidazolyl.
  • R 2 is 1-methylimidazol-4-yl, or 5-(hydroxymethyl)-1- methylimidazol-2-yl.
  • R 2 is 1-methylimidazol-4-yl. [0078] In some embodiments, R 2 is 5-(hydroxymethyl)-1-methylimidazol-2-yl. [0079] In some embodiments, R 2 is substituted triazolyl. [0080] In some embodiments, R 2 is 1-methyl-1,2,3-triazol-4-yl. [0081] In some embodiments, R 2 is substituted furanyl. [0082] In some embodiments, R 2 is 2-(hydroxymethyl)furan-5-yl. [0083] In some embodiments, R 2 is substituted thiophenyl. [0084] In some embodiments, R 2 is 2-(hydroxymethyl)thiophen-5-yl.
  • R 2 is substituted pyridinyl. [0086] In some embodiments, R 2 is 2-(hydroxymethyl)pyridin-4-yl. [0087] In some embodiments, R 2 is substituted pyrimidinyl. [0088] In some embodiments, R 2 is optionally substituted cycloalkyl. [0089] In some embodiments, R 2 is optionally substituted C 1 -C 6 -alkyl-cycloalkyl. [0090] In some embodiments, R 2 is optionally substituted C 1 -C 6 -alkyl. [0091] In some embodiments, R 2 is optionally substituted heterocycloalkyl.
  • n in the compounds of formula (I) is 1, 2, or 3.
  • n is 1.
  • n is 2.
  • n is 3.
  • R 3 and R 4 in the compounds of formula (I) are each independently optionally substituted aryl, optionally substituted heteroaryl, optionally (ACT6051WOPCT1) substituted alkyl, optionally substituted cycloalkyl, optionally substituted spirocycloalkyl, or optionally substituted heterocycloalkyl; or one of R 3 or R 4 may be H.
  • R 3 or R 4 is optionally substituted aryl.
  • R 3 or R 4 is optionally substituted heteroaryl. [0099] In some embodiments, R 3 or R 4 is optionally substituted alkyl. [00100] In some embodiments, R 3 or R 4 is methyl. [00101] In some embodiments, R 3 or R 4 is isopropyl. [00102] In some embodiments, R 3 or R 4 is optionally substituted cycloalkyl. [00103] In some embodiments, R 3 or R 4 is optionally substituted spirocycloalkyl. [00104] In some embodiments, R 3 or R 4 is optionally substituted heterocycloalkyl.
  • R 3 or R 4 is tetrahydropyran-4-yl.
  • one of R 3 or R 4 in compounds of formula (I) is H.
  • R 3 is optionally substituted C 1 -C 6 alkyl and R 4 is optionally substituted heterocycloalkyl.
  • R 3 is methyl and R 4 is optionally substituted heterocycloalkyl.
  • R 3 is methyl and R 4 is tetrahydropyran-4-yl.
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form an optionally substituted 3-12-membered heterocycloalkyl ring.
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form an optionally substituted 4-6-membered heterocycloalkyl ring.
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form an optionally substituted 3-12-membered heterocycloalkyl ring (ACT6051WOPCT1) [00114] In some embodiments, R 3 and R 4 , together with the nitrogen atom to which they are both attached, form a piperidinyl group, . [00115] In some embodiments, R 3 and R 4 , together with the nitrogen atom to which they are both attached, form a 2,2-dimethylpyrrolidin-1-yl group, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form a 3,3-dimethylazetidin-1-yl group, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form a 2,2-dimethylazetidin-1-yl group, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form a 2-methyl-pyrrolidin-1-yl group, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form a (R)-2-methyl-pyrrolidin-1-yl group, .
  • R 3 and R 4 together with the nitrogen atom to which .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form a 3-methyl-pyrrolidin-1-yl group, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form a (R)-3-methyl-pyrrolidin-1-yl group.
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form a (S)-3-methyl-pyrrolidin-1-yl group, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form (R)-3-methyl-pyrrolidin-1-yl, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form a morpholin-4-yl, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form 2-ethyl-morpholin-4-yl, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form (S)-2-ethyl-morpholin-4-yl. (ACT6051WOPCT1) [00128] In other embodiments, R 3 and R 4 , together with the nitrogen atom to which they are both attached, form (R)-2-ethyl-morpholin-4-yl. [00129] In other embodiments, R 3 and R 4 , together with the nitrogen atom to which they are both attached, form 2-methyl-morpholin-4-yl, .
  • R 3 and R 4 together with the nitrogen atom to which O (S) N they are both attached, form (S)-2-methyl-morpholin-4-yl, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form (R)-2-methyl-morpholin-4-yl.
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form 3-methyl-morpholin-4-yl, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form (R)-3-methyl-morpholin-4-yl, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form (S)-3-methyl-morpholin-4-yl.
  • R 3 and R 4 together with the nitrogen atom to which OMe N they are both attached, form .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form . (ACT6051WOPCT1)
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form 3,5-dimethyl-morpholin-4-yl, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form (3R,5R)-3,5-dimethyl-morpholin-4-yl, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form (3S,5R)-3,5-dimethyl-morpholin-4-yl.
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form 2,6-dimethyl-morpholin-4-yl, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form (2R,6R)-2,6-dimethyl-morpholin-4-yl.
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form (2S,6R)-2,6-dimethyl-morpholin-4-yl.
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form an optionally substituted 5-12-membered bridged heterocycloalkyl ring.
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form an optionally substituted 8-membered bridged heterocycloalkyl ring.
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form a 2-azabicyclo[2.2.2]octanyl group, . ⁇ ACT6051WOPCT1)
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form an 3-oxa-8-azabicyclo[3.2.1]octan-8-yl group, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form an optionally substituted 4-12-membered fused heterocycloalkyl ring system.
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form an optionally substituted 6-7-membered fused heterocycloalkyl ring system.
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form a 3-azabicyclo[3.2.0]heptanyl group: .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form a 3-azabicyclo[3.1.0]hexanyl group: .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form an optionally substituted 5-12-membered spiroheterocycloalkyl ring system.
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form an optionally substituted 7-9-membered spiroheterocycloalkyl ring. ⁇ ACT6051WOPCT1) [00156] In some embodiments, R 3 and R 4 , together with the nitrogen atom to which they are both attached, form a 4-azaspiro[2.4]heptan-4-yl group, . [00157] In some embodiments, R 3 and R 4 , together with the nitrogen atom to which they are both attached, form a 5-azaspiro[2.4]heptan-5-yl group, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form a 5-azaspiro[3.4]octan-5-yl group, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form a 6-azaspiro[3.4]octan-6-yl group, .
  • R 3 and R 4 together with the nitrogen atom to which they are both attached, form a 2-oxa-5-azaspiro[3.4]octan-5-yl group, .
  • each R 5 and each R 6 is independently H, C 1 -C 6 alkyl, or C 3 -C 5 cycloalkyl.
  • an R 5 or an R 6 is H.
  • an R 5 or an R 6 is C 1 -C 6 alkyl, such as, for example, C 6 alkyl, C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl, C 1 alkyl, methyl, ethyl, and the like.
  • an R 5 or an R 6 is C 3 -C 5 cycloalkyl, such as, for example, C 5 cycloalkyl, C 4 cycloalkyl, C 3 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • each R 5 and each R 6 is H.
  • an R 5 or R 6 in the compounds of formula (I), together with an R 3 or R 4 form an optionally substituted 3-12-membered heterocycloalkyl ring, an optionally substituted 5-12-membered bridged heterocycloalkyl ring, an optionally substituted 4-12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12-membered spiroheterocycloalkyl ring system.
  • an R 5 or R 6 together with an R 3 or R 4 form an optionally substituted 4- or 5-membered heterocycloalkyl ring, such as, for example, an optionally substituted azetidnyl ring, or an optionally substituted pyrrolidinyl ring.
  • an R 5 or R 6 together with an R 3 or R 4 form an optionally substituted 3-12-membered heterocycloalkyl ring.
  • the structure formula (I) is (ACT6051WOPCT1) [00172] In other embodiments of the compounds of formula (I) wherein an R 5 or R 6 , together with an R 3 or R 4 may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00173] In other embodiments of the compounds of formula (I) wherein an R 5 or R 6 , together with an R 3 or R 4 may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00174] In some aspects, L is -C(O)NH-, -NHC(O)-, or -NHC(O)NH, wherein when n is 1, L is -NHC(O)-.
  • L is -NHC(O)-.
  • L is -C(O)NH-.
  • L is -NHC(O)NH-.
  • the diradicals “-L-,” as used herein, are written from left-to-right such that the left hand side of L is attached to the pyridinyl moiety in the compounds of the disclosure.
  • n is 1 and L is - NHC(O)-.
  • n is 2 and L is - NHC(O)-.
  • n is 2 and L is - C(O)NH-.
  • n is 2 and L is - NHC(O)NH-.
  • the compound of formula (I) is a compound of formula (IA): or a pharmaceutically acceptable salt thereof, wherein Q is N or CH; R 7 is H, C1-C6alkyl, C3-C6cycloalkyl, halogen, -CN, or C1-C4fluoroalkyl; and R 8 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen, or C 1 -C 4 fluoroalkyl, and the other variables are as described above for the compound of formula (I). [00184] In some embodiments of the compound of formula (IA), Q is N.
  • R 7 is H.
  • R 7 is C 1 -C 6 alkyl.
  • R 7 is C 3 - C 6 cycloalkyl.
  • R 7 is halogen, such as, for example, -F, -Cl, -Br, or -I.
  • R 7 is -CN.
  • R 7 is C 1 - C 4 fluoroalkyl.
  • R 8 is H. (ACT6051WOPCT1) [00193] In other embodiments of the compound of formula (IA), R 8 is C 1 -C 6 alkyl. [00194] In other embodiments of the compound of formula (IA), R 8 is C 3 - C 6 cycloalkyl. [00195] In other embodiments of the compound of formula (IA), R 8 is halogen, such as, for example, -F, -Cl, -Br, or -I.
  • the compounds according to formula (I) are those that have an IC 50 ⁇ 20 nM in a PDGFR cellular assay such as, for example, that described in the Experimental section below.
  • (ACT6051WOPCT1) [00201] In some embodiments, the compounds according to formula (I) are those that have an IC 50 ⁇ 5 nM in a PDGFR cellular assay such as, for example, that described in the Experimental section below.
  • the compound of the disclosure is one of Examples 1-58 described herein, or a pharmaceutically acceptable salt thereof.
  • Stereoisomers of compounds of formula (I) are also contemplated by the present disclosure.
  • the disclosure encompasses all stereoisomers and constitutional isomers of any compound disclosed or claimed herein, including all enantiomers and diastereomers.
  • Pharmaceutically acceptable salts and solvates of the compounds of formula (I) are also within the scope of the disclosure.
  • Isotopic variants of the compounds of formula (I) are also contemplated by the present disclosure.
  • References to compounds of formula (I) herein include the compounds of formula (I) and subgenera thereof (e.g., formula (IA), formula (IA-1), formula (IA-2)) disclosed herein.
  • compositions and methods of administration are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
  • the pharmaceutical compositions contain a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions.
  • the one or more compounds of the invention and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.
  • the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range
  • the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 5%,
  • the concentration of one or more compounds of the invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to (ACT6051WOPCT1) approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v.
  • the concentration of one or more compounds of the invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.
  • the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009
  • the amount of one or more compounds of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g,
  • the amount of one or more compounds of the invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.
  • the compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per (ACT6051WOPCT1) day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg per day.
  • the amount of the compounds described herein are set forth on a free base basis. That is, the amounts indicate that amount of the compound administered, exclusive of, for example, solvent (such as in solvates) or counterions (such as in pharmaceutically acceptable salts).
  • solvent such as in solvates
  • counterions such as in pharmaceutically acceptable salts.
  • the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration.
  • the composition further contains: (iv) an effective amount of a third agent.
  • the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption.
  • compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in- water emulsion, or a water-in-oil liquid emulsion.
  • dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients.
  • compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet can be prepared by compression or molding, optionally (ACT6051WOPCT1) with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds.
  • water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf- life or the stability of formulations over time.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
  • An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose.
  • suitable carriers include (ACT6051WOPCT1) powders, capsules, and tablets, with the solid oral preparations.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrol
  • suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle.
  • Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form.
  • a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein.
  • the amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition.
  • Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
  • Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other (ACT6051WOPCT1) glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof.
  • a lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.
  • the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • the tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • Surfactant which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed. [00231] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10.
  • HLB hydrophilic-lipophilic balance
  • Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
  • Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
  • lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10.
  • HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
  • Hydrophilic surfactants may be either ionic or non-ionic.
  • Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di- glycerides; and mixtures thereof.
  • ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
  • Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP -phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, capry
  • Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and
  • the polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
  • Other hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG- 10
  • Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof.
  • preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.
  • the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, e.g., compositions for injection.
  • a solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
  • suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as te
  • solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N- methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.
  • solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • the amount of solubilizer that can be included is not particularly limited.
  • the amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art.
  • the solubilizer can be in a weight ratio of 10%, 25%o, 50%), 100%o, or up to about 200%> by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%>, 2%>, 1%) or even less. Typically, the solubilizer may be present in an amount of about 1%> to about 100%, more typically about 5%> to about 25%> by weight.
  • the composition can further include one or more pharmaceutically acceptable additives and excipients.
  • additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons.
  • Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, (ACT6051WOPCT1) ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like.
  • amino acids amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, (ACT6051WOPCT1) ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisoprop
  • bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para- bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.
  • a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids
  • Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used.
  • the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like.
  • Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.
  • Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.
  • suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like.
  • compositions for injection [00246]
  • the invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein.
  • the forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
  • ACT6051WOPCT1 Aqueous solutions in saline are also conventionally used for injection.
  • Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • certain desirable methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Pharmaceutical compositions for topical (e.g. transdermal) delivery are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • certain desirable methods of preparation are vacuum-drying and freeze
  • the invention provides a pharmaceutical composition for transdermal delivery containing a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.
  • Compositions of the present invention can be formulated into preparations in solid, semisolid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions.
  • DMSO dimethylsulfoxide
  • carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients.
  • a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.
  • the pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability (ACT6051WOPCT1) barrier of the skin. There are many of these penetration- enhancing molecules known to those trained in the art of topical formulation.
  • humectants e.g., urea
  • glycols e.g., propylene glycol
  • alcohols e.g., ethanol
  • fatty acids e.g., oleic acid
  • surfactants e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.glycerol monolaurate, sulfoxides, terpenes (e.g., menthol)
  • amines amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, either with or without another agent.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos.5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Pharmaceutical compositions for inhalation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • compositions for inhalation may be delivered as a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
  • a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
  • a pressurised container, pump, spray, atomizer or nebuliser with or without the use of a suitable propellant.
  • the inhalation device may be an aerosol vial provided with a valve adapted to deliver a metered dose, i.e. a metered dose inhaler.
  • the inhalation device may be a nebulizer, such as an airjet nebulizer, or an ultrasonic nebulizer, or a hand- held nebulizer, sometimes referred to as a soft mist or soft spray inhaler, or a mechanical device which allows much smaller nebulized volumes than conventional nebulizers.
  • a nebulizer such as an airjet nebulizer, or an ultrasonic nebulizer, or a hand- held nebulizer, sometimes referred to as a soft mist or soft spray inhaler
  • a mechanical device which allows much smaller nebulized volumes than conventional nebulizers.
  • Such devices are referred to in, for example, WO2013030802.
  • the inhalation device may be, for example, a dry powder inhalation device adapted to deliver dry powder from a capsule or blister containing a dry powder comprising a dosage unit or a multidose dry powder inhalation (MDPI) device adapted to deliver dry powder comprising a dosage unit upon actuation.
  • the dry powder composition preferably contains a diluent or carrier, such as lactose, and a compound that helps to protect against product performance deterioration due to moisture e.g. magnesium stearate.
  • the invention also includes (A) a compound of the invention, or a pharmaceutically acceptable salt thereof, in inhalable form; (B) an inhalable medicament comprising the compound in inhalable form together with a pharmaceutically acceptable carrier in inhalable form; (C) a pharmaceutical product comprising such a compound in inhalable form in association with an inhalation device; and (D) an inhalation device containing such a compound in inhalable form.
  • A a compound of the invention, or a pharmaceutically acceptable salt thereof, in inhalable form
  • B an inhalable medicament comprising the compound in inhalable form together with a pharmaceutically acceptable carrier in inhalable form
  • C a pharmaceutical product comprising such a compound in inhalable form in association with an inhalation device
  • D an inhalation device containing such a compound in inhalable form.
  • Other pharmaceutical compositions include (A) a compound of the invention, or a pharmaceutically acceptable salt thereof, in inhalable form; (B) an inhalable medicament comprising the compound in in
  • compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art.
  • Administration of the compounds or pharmaceutical composition of the present invention can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally. [00263] The amount of the compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician.
  • an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. by dividing such larger doses into several small doses for administration throughout the day. [00264] In some embodiments, a compound of the invention is administered in a single dose.
  • a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once per day to about 6 times per (ACT6051WOPCT1) day.
  • a compound of the invention in another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary. [00267] Administration of the compounds of the invention may continue as long as necessary. In some embodiments, a compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
  • compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty.
  • compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis.
  • a compound of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent.
  • a compound of the invention is admixed with a matrix.
  • a matrix may be a polymeric matrix, and may serve to bond the compound to the stent.
  • Polymeric matrices suitable for such use include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g. polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters.
  • lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copo
  • Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds.
  • Compounds of the ⁇ ACT6051WOPCT1) invention may be applied to the surface of the stent by various methods such as dip/spin coating, spray coating, dip-coating, and/or brush-coating.
  • the compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent.
  • the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall.
  • Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash.
  • compounds of the invention may be covalently linked to a stent or graft.
  • a covalent linker may be used which degrades in vivo, leading to the release of the compound of the invention. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages.
  • Compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty.
  • Extravascular administration of the compounds via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis.
  • a variety of stent devices which may be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U.S. Pat. No.5451233; U.S. Pat. No.5040548; U.S. Pat. No.5061273; U.S. Pat. No. 5496346; U.S. Pat. No.5292331; U.S. Pat. No.5674278; U.S. Pat. No.3657744; U.S. Pat. No.4739762; U.S. Pat. No.5195984; U.S.
  • the compounds of the invention may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation in light of the instant disclosure.
  • a compound of the invention is administered in a composition that comprises one or more agents, and the agent has a shorter half- life than the compound of the invention unit dose forms of the agent and the compound of the invention may be adjusted accordingly.
  • the subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release (ACT6051WOPCT1) formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
  • Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • Methods of Use [00275] The method typically comprises administering to a subject a therapeutically effective amount of a compound of the invention.
  • the therapeutically effective amount of the subject combination of compounds may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downregulation of activity of a target protein.
  • the specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • the disclosure also relates to methods of using the compounds described herein to treat in a subject in need thereof, a disease or disorder in which PDGFR signaling is implicated. These methods are accomplished by administering to the subject a compound of the disclosure in an amount effective to treat the disease or disorder.
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is pulmonary hypertension (PH).
  • the pulmonary hypertension is pulmonary arterial hypertension (PAH) (WHO PH Group 1); PH secondary to heart failure (WHO PH Group 2); PH secondary to lung diseases and/or hypoxia (WHO PH Group 3); PH due to pulmonary (ACT6051WOPCT1) artery obstruction (WHO Group 4); or PH due to unknown or rare diseases (WHO PH Group 5).
  • PAH pulmonary arterial hypertension
  • WHO PH Group 1 PH secondary to heart failure
  • WHO PH Group 3 PH secondary to lung diseases and/or hypoxia
  • WHO PH Group 4 PH due to pulmonary
  • PH due to unknown or rare diseases WHO PH Group 5
  • the PAH (WHO PH Group 1) is idiopathic PAH, PAH with vasoreactivity, heritable PAH, drugs and toxins-induced PAH, PAH associated with connective tissue disease, PAH associated with HIV infection, PAH associated with portal hypertension, PAH associated with congenital heart disease, PAH associated with schistosomiasis, PAH in long-term responders to calcium channel blockers, PAH with overt signs of venous/capillaries involvement; persistent PH of the Newborn syndrome; or systemic sclerosis-associated PAH (SSc-PAH).
  • SSc-PAH systemic sclerosis-associated PAH
  • the PAH secondary to heart failure (WHO PH Group 2) is PH due to heart failure with preserved ejection fraction, PH due to heart failure with reduced ejection fraction, valvular heart disease, or congenital post-capillary obstructive lesions.
  • the PH secondary to lung diseases and/or hypoxia (WHO PH Group 3) is PH due to obstructive lung disease, PH due to restrictive lung disease, PH due to other lung diseases with mixed restrictive/obstructive pattern, PH due to hypoxia without lung disease, PH due to developmental lung disorders.
  • the PH due to obstructive lung disease is PH due to chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the PH due to restrictive lung disease is PH due to interstitial lung diseases (ILDs).
  • the PH due to interstitial lung diseases (ILDs) is PH due to idiopathic pulmonary fibrosis (IPF).
  • the PH due to pulmonary artery obstruction is chronic thromboembolic PH (CTEPH) or PH due to other pulmonaty artery obstructions.
  • the PH due to unknown or rare diseases is PH due to hematologic disorders, PH due to systemic disorders, PH due to other disorders, or PH due to complex congenital heart disease.
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is a respiratory disease.
  • the respiratory disease is asthma.
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is a fibrotic disease.
  • the fibrotic disease is pulmonary fibrosis, cardiac fibrosis or liver fibrosis. [00291] In some embodiments, the fibrotic disease is pulmonary fibrosis. [00292] In some embodiments, the pulmonary fibrosis is an interstitial lung disease. [00293] In some embodiments, the interstitial lung disease is idiopathic pulmonary fibrosis. [00294] In some embodiments, the interstitial lung disease is rheumatoid arthritis- associated interstitial lung disease. [00295] In some embodiments, the interstitial lung disease is systemic sclerosis- associated interstitial lung disease.
  • the interstitial lung disease is connective tissue disease-associated interstitial lung disease. [00297] In some embodiments, the interstitial lung disease is nonspecific interstitial pneumonia. [00298] In some embodiments, the interstitial lung disease is unclassifiable interstitial lung disease. [00299] In some embodiments, the interstitial lung disease is hypersensitivity pneumonitis. [00300] In some embodiments, the interstitial lung disease is sarcoidosis. [00301] In some embodiments, the interstitial lung disease is non-idiopathic pulmonary fibrosis interstitial lung disease.
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is a dermatological disease.
  • the dermatological disease or disorder is atopic dermatitis, scleroderma, or urticaria.
  • ACT6051WOPCT1 atopic dermatitis, scleroderma, or urticaria.
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is an inflammatory disease or disorder.
  • the inflammatory disease or disorder is allergic rhinitis, irritable bowel syndrome (IBS); or inflammatory bowel disease (IBD).
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is an autoimmune disorder.
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is a metabolic disease.
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is vascular restenosis; age-related macular degeneration (AMD); irritable bowel syndrome (IBS); inflammatory bowel disease (IBD); obesity-cell related diseases; type I diabetes or type II diabetes.
  • AMD age-related macular degeneration
  • IBS irritable bowel syndrome
  • IBD inflammatory bowel disease
  • obesity-cell related diseases type I diabetes or type II diabetes.
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH secondary to heart failure (WHO PH Group 2).
  • WHO PH Group 2 PH secondary to heart failure
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH due to heart failure with preserved ejection fraction.
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH due to heart failure with reduced ejection fraction.
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is valvular heart disease. (ACT6051WOPCT1)
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is congenital post-capillary obstructive lesions.
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH secondary to lung diseases and/or hypoxia (WHO PH Group 3).
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH due to pulmonary artery obstruction (WHO Group 4).
  • WHO Group 4 pulmonary artery obstruction
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is chronic thromboembolic PH (CTEPH).
  • CTEPH chronic thromboembolic PH
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH due to unknown or rare diseases (WHO PH Group 5).
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is idiopathic PAH.
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PAH associated with connective tissue disease.
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is systemic sclerosis-associated PAH (SSc-PAH).
  • SSc-PAH systemic sclerosis-associated PAH
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH secondary to interstitial lung diseases (ILDs).
  • ILDs interstitial lung diseases
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH secondary to chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH secondary to idiopathic pulmonary fibrosis (IPF).
  • an effective amount of a pharmaceutical agent according to the disclosure is administered to a subject suffering from or diagnosed as having such a disease or disorder.
  • An "effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in patients in need of such treatment for the designated disease or disorder.
  • Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease or disorder, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.
  • An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID).
  • an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.
  • the compounds of the disclosure may be used in combination with additional active ingredients in the treatment of the above diseases or disorders.
  • the additional active ingredients may be coadministered separately with a compound of the disclosure or included with such an agent in a pharmaceutical composition according to the disclosure.
  • the combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the disclosure), decrease one or more side effects, or decrease the required dose of the active agent according to the disclosure.
  • references herein to methods of treatment using one or more compounds or formulations thereof should also be interpreted as references to: (i) one or more compounds or formulations thereof for use in methods of treatment; and/or (ii) the use of one or more compounds or formulations thereof in the manufacture of a medicament for treating a pathological condition.
  • (ACT6051WOPCT1) [00328]
  • Compounds of formula (I) in the present invention can be synthesized in accordance with general synthetic methods familiar to those who are skilled in the art. The following reaction schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention.
  • Scheme 1 [00329] Scheme 1 illustrated the synthesis of Formula I.
  • the acid (I-1) was first coupled with an amine (I-2), a couple agent such as HATU, a base such as TEA in a solvent such as DMF to give compound (I-3).
  • a couple agent such as HATU
  • a base such as TEA
  • a solvent such as DMF
  • the cyano containing compound (I-4) treated with alkylhydrazine (I-5) in a solvent with a base such as sodium carbonate an amine compound (I-6) which then treated with boronated agent (I-7), a catalyst such as PdCl 2 (dppf).CH 2 Cl 2 , a base such as Cs 2 CO 3 and a solvent such as dioxane-water to yield compound (I-8).
  • the amine (I-8) was then coupled with compound (I-3), a couple agent such as Brettphos-Pd-G3, a ligand such as Brettphos, a base such as Cs 2 CO 3 in a solvent such as DMF to give Formula I.
  • a couple agent such as Brettphos-Pd-G3, a ligand such as Brettphos, a base such as Cs 2 CO 3 in a solvent such as DMF to give Formula I.
  • Step b 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine solution of 2-(2, 2-dimethylpyrrolidin-1-yl)acetonitrile (22 g, 159.18 mmol) in THF (400 mL) was added lithium aluminium hydride (7.25 g, 191.01 mmol) by portions at 0 °C (ice/water). The resultant mixture was stirred at 20 °C for 4 hours before quenched with water (7.25 g) at 0 °C. The reaction mixture was filtered. And the filtration was concentrated to dryness under reduced pressure to afford the crude product 2-(2, 2- dimethylpyrrolidin-1-yl)ethanamine a yellow oil.
  • Step c.5-bromo-N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6-methylnicotinamide (ACT6051WOPCT1) [00332] A solution of 5-bromo-6-methylnicotinic acid (575 mg, 2.66 mmol) and 2- (3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1822 mg, 4.79 mmol) in DMF (10 mL) was stirred at room temperature for 15 minutes.
  • the reaction mixture was purged with N 2 for 2 minutes. The reaction mixture was stirred at 100°C for 15 hrs.
  • the (ACT6051WOPCT1) reaction mixture was purified by Prep-HPLC. column: Boston Green ODS 150*30mm*5um; Condition: A: water (0.225%FA), B: MeCN; at the beginning: A (95%) and B (5%), at the end: A (65%) and B (35%); Gradient Time(min) 7; 100%B Hold Time(min) 3; Flow Rate(ml/min) 35. The pure fractions were collected, and the solvent was evaporated under vacuum, lyophilized to dryness to give the title compound (45 mg) as an off-white solid.
  • Reagents (ACT6051WOPCT1) [00350] Instrumentation: a. Compound liquid handling: LabCyte Echo; b. Reagent liquid handling: Thermo Scientific Multidrop Combi; c. BMG PHERAStar multilabel plate reader. [00351] Protein Reagent: His6-TEV-PDGFR ⁇ Protein Prep prepared at Accelagen. [00352] II.
  • TK-biotin peptide 0.5 ⁇ M in molecular biology grade water, store at - 20°C in aliquots.
  • ATP 100 mM in molecular biology grade water, store at -20°C in aliquots.
  • HTRF KinEASE-TK kit Allow the contents of the Cisbio kit to warm up to room temperature before use. This kit contains HTRF detection buffer, TK-Antibody labeled with Eu 3+- cryptate, TK-substrate biotin and Streptavidin-XL665.
  • TK Substrate-Biotin reconstitute 500 ⁇ g lyopholized with 574 ⁇ L molecular biology grade water to prepare a 500 ⁇ M stock; After use, aliquot the rest and store at -20°C.
  • TK Antibody-Cryptate reconstitute lyophilized with 1 mL of molecular biology grade water (100x solution) then add 99 mL detection buffer to prepare a ready to use TK-antibody-cryptate solution; the concentration of the TK-antibody-cryptate reagent is not known. After use, aliquot the rest and store at -20°C.
  • [00363] Streptavidin-XL665, reconstitute 3 mg lyophilized with 3 mL molecular biology grade water to prepare a 1 mg/mL or 16.67 ⁇ M stock; MW 60 kDa; After use, aliquot the rest and store at -20°C. [00364] Freshly prepared solutions: [00365] Assay buffer. Dilute 5x Kinase buffer 5-fold with molecular biology grade water and add DTT to 2 mM and ovalbumin to 0.1 mg/mL (or 0.01%). [00366] 2X protein solution. Make a working solution of 100 pM PDGFR ⁇ in assay buffer. Keep on ice until use to maintain enzyme stability. [00367] 2X substrate solution.
  • Dispensing inhibitors/DMSO and low control Using the ECHO 555 acoustic dispenser, spot desired compound serial dilutions in DMSO, NEAT DMSO to represent the uninhibited enzyme control, and 10 ⁇ M final [imatinib] to the represent the 100% inhibited enzyme control [00378] Step 2.
  • PDGFR ⁇ E + I pre-incubation Add 2 ⁇ L 2x protein solution to columns 1-24 using the Multidrop Combi. Centrifuge at 1000 rpm for 1 min. Incubate 30 min at RT [00379] Step 2.
  • Enzymatic reaction Add 2 ⁇ L substrate solution to columns 1-24 to initiate the reaction using the Multidrop Combi; cover/seal the assay plate to reduce evaporation.
  • HTRF ratio values calculated by the instrument (Ratio is acceptor counts/donor counts * 10,000) is exported from the plate reader and used in data analysis. The exported data will be used to calculate 1) compound activity and 2) assay statistics.
  • Compound activity is represented by % Inhibition when testing a single dose of a compound or IC50 when testing a dose response of a compound.
  • Assay statistics can include Robust Z’ and Signal to Background.
  • PDGFR ⁇ LanthaScreen assay [00406] I. Materials (ACT6051WOPCT1) [00407] II. Methods and Procedures [00408] Stock solutions: [00409] Assay buffer stock contains 50 mM HEPES pH7.5, 10 mM MgCl 2 , 0.01% Brij- 35, 1 mM EGTA. [00410] Tb-labeled inactive PDGFR ⁇ .3.6 ⁇ M in 50 mM HEPES, pH 7.4, 150 mM NaCl, 0.005% Tween-20 and 10% glycerol. Store at -80 o C in aliquots.
  • % Inhibition (NC – sample) / (NC – PC) * 100 where NC is the mean of negative control (reactions without inhibitor), and PC is the mean of positive control (1 ⁇ M sunitinib).
  • PDGFR ⁇ cellular assay [00427] I. Materials [00428] II. Methods and Procedures [00429] Cell Culture and Preparation: Cells are cultured according to ATCC procedure (5) with the addition of the antibiotic penicillin-streptomycin. If working from frozen, cells should be thawed according to ATCC procedure. Depending on the cell density of frozen vial, cells will need time to recover from thaw. An 80% confluent T75 flask should be enough for one 384 well plate. [00430] Stock Solutions: Rat PDGFBB. A 100ug/mL stock is prepared by reconstituting 50ug in 500uL of 4mM HCl and 0.1% BSA.
  • Freshly Prepared Solutions [00432] 1x Cisbio cell lysis buffer. The cell lysis buffer is diluted 4-fold with molecular grade water. The blocking agent is then diluted 25-fold in the diluted lysis buffer. [00433] Antibody solutions. Equal amounts d2 and cryptate antibody are diluted 20-fold in detection buffer. (ACT6051WOPCT1) [00434] Rat PDGFBB. A working stock of 100ng/mL is created from the stock solution in 10%FBS culture media.
  • Step 1 Plating Cells: Media from the A10 cell flask is aspirated. The cells are rinsed with PBS and then trypsinized to disperse the cell layer. The cells are then pelleted are resuspended to 1.25e5 cells/mL. 40uL of cells are then plated in 384 Greiner TC treated plates at a density of 5000 cells/well using the Combi. Plates are covered and placed in the incubator (37°C 5% CO2) overnight to allow cells to adhere.
  • Step 2 Compound Dispense: Approximately 18 hours after plating, dispense 40nL compound onto cells using Echo.
  • Step 3 Activation by PDGFbb: 6uL of the working stock of 100ng/mL PDGFbb is dispensed using the Tempest to give a final assay concentration of 15ng/mL (EC80). After 10 minutes the media is removed by flicking the plate.
  • Step 4 Cell lysis and antibody addition: 20uL lysis buffer per well is added to the plate via Tempest. 5uL antibody solution is added per well via the Tempest. The plate is placed on the shaker at 230 rpm for 1 hour at room temperature.
  • VEGFR ADP GLO assay [00445] I. Materials (ACT6051WOPCT1) [00446] II. Methods and Procedures [00447] Stock solutions: [00448] Assay buffer stock contains 50mM HEPES pH7.5, 10mM MgCl 2 , 0.01% Brij-35, and 1mM EGTA.
  • Step 2 Pre-incubation of inhibitors with kinase: Add 2 ⁇ L/well 2X kinase solution. Centrifuge at 1000 rpm for 1 min. Incubate at room temperature for 30 min.
  • Step 3 Kinase cascade reaction: Add 2 ⁇ L/well 2X substrate/ATP solution to initiate kinase reactions.
  • % Inhibition (NC – sample) / (NC – PC) * 100 where NC is the mean of negative control (reactions without inhibitor), and PC is the mean of positive control (1 ⁇ M TAK-593).
  • IC50 determination Compounds are serially diluted 3-fold and tested in an 11- point dose response.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pulmonology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The disclosure is directed to compounds of formula (I) and pharmaceutically acceptable salts thereof. Pharmaceutical compositions comprising compounds of formula (I), as well as methods of their use and preparation, are also described.

Description

(ACT6051WOPCT1) PYRAZOLOPYRROLOPYRIDAZINES AND THEIR USES AS PDGFR INHIBITORS CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of United States Provisional Application No.63/425,024, filed November 14, 2022, the entirety of which is incorporated by reference herein. TECHNICAL FIELD [0002] The disclosure is directed to PDGFR inhibitors and methods of their use. BACKGROUND [0003] Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins. Protein kinases play a critical role in the control cell growth, proliferation, differentiation, metabolism, apoptosis, cell mobility, transcription, translation and other signaling processes. The overexpression or inappropriate expression of protein kinases plays a significant role in the development of many diseases and disorders including central nervous system disorders, inflammatory disorders, metabolic disorders, autoimmune diseases, cardiovascular diseases, fibrotic diseases, transplantation rejection, cancer and infectious diseases. [0004] Growth factors (GF) are important regulators of human homeostasis involved in maintaining a delicate balance between cell growth, differentiation, and proliferation. Consequently, dysregulation of GF signaling are implicated in many diseases including oncology, immunology, fibroproliferative, cardiovascular, vascular disorders and pulmonary hypertension. GF bind to several different receptors that amplify the signal through activation of the specific receptor through phosphorylation, leading to confirmation changes increasing the affinity for ATP and the phosphorylation of downstream proteins leading to activation of several signaling cascades. Therefore, small changes in GF or the cognate receptors can significantly alter the local signaling and have dramatic effects on initiation and progression of many diseases. [0005] Platelet-derived growth factor (PDGF) is one of many GFs that regulate cell growth and division. PDGF exerts its biological responses via activation of two highly specific, transmembrane receptor tyrosine kinases, termed PDGFR α and PDGFR β, which (ACT6051WOPCT1) can form three different dimeric receptors – αα, ββ and αβ. These receptors can interact with the different dimeric PDGF ligands (PDGF-AA, PDGF-BB, PDGF-CC, PDGF-DD and PDGF-AB) with different specificities and efficacies. The receptors are activated by ligand- induced dimerization, leading to autophosphorylation on specific tyrosine residues. PDGFR phosphorylation recruits signaling proteins containing Tyr(P)-binding domains. Several of these signaling proteins include Src kinase family members, phospholipase C-y1, the p38a subunit of PI3K, GTPase-activating protein. The formation of receptor-signaling complexes then initiates the activation of various signaling pathways, including the Ras-mitogen activated protein (MAP) kinase pathway, the PI3kinase-Akt pathway, the PLC-y1 and the Src pathway. Activation of PDGFRα or PDGFRβ by PDGFs, leads to protein synthesis, proliferation, migration, protection against apoptosis and cellular transformation, key mechanisms associated with several vascular diseases including pulmonary hypertension. Platelet-derived growth factor (PDGF) and its receptors (PDGFR), including PDGFRα and PDGFRβ, play important roles in tumorigenesis, tumor progression, and the regulation of stromal cell function. Constitutive activation of PDGFR signaling, gene rearrangement, and activating mutations of PDGFR have been identified in various types of human tumors and malignancies. [0006] PDGFR signaling is implicated in the development and progression of pulmonary hypertension. PDGFs are expressed in ECs, SMCs and macrophages and are strong mitogens and chemokines. Increased signaling through PDGFRβ leads to smooth muscle cell proliferation which contributes to the development of vascular remodeling. PDGF and PDGF receptors (α and β) are upregulated in human and animals with pulmonary hypertension. Preclinically, efficacy in preventing and reversing vascular remodeling in experimentally induced pulmonary hypertension was demonstrated through non-selective inhibition of PDGF receptors. Clinically, imatinib (also known as Gleevec), a non-selective tyrosine kinase inhibitor including PDGF receptors improved exercise capacity and hemodynamics in patients with advanced pulmonary hypertension. Conversely, dasatinib, a receptor tyrosine kinases inhibitor, was linked to cardiotoxicity and the development of pulmonary hypertension, emphasizing the importance of the appropriate kinase selectivity, and associated differentiated profile. [0007] A need exists for additional PDGFR inhibitors for the treatment of pulmonary hypertension and other conditions in which PDGFR signaling is implicated. (ACT6051WOPCT1) SUMMARY [0008] The present disclosure provides PDGFR inhibitors. [0009] In some aspects, the present disclosure provides compounds of formula (I):
Figure imgf000004_0001
or pharmaceutically acceptable salts thereof, wherein A is an optionally substituted phenyl ring or an optionally substituted pyridinyl ring; R1 is optionally substituted C1-C6alkyl or optionally substituted C3-C5cycloalkyl; R2 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted C1-C6-alkyl-cycloalkyl, optionally substituted C1-C6-alkyl, or optionally substituted heterocycloalkyl; n is 1, 2, or 3; R3 and R4 are each independently optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted spirocycloalkyl, or optionally substituted heterocycloalkyl; or one of R3 or R4 may be H; or R3 and R4 , together with the nitrogen atom to which they are both attached, form an optionally substituted 3-12-membered heterocycloalkyl ring, an optionally substituted 5- 12-membered bridged heterocycloalkyl ring, an optionally substituted 4- 12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12- membered spiroheterocycloalkyl ring system, wherein said 3-12-membered heterocycloalkyl ring, 5-12- membered bridged heterocycloalkyl ring, 4-12-membered fused heterocycloalkyl ring system, or 5-12-membered spiroheterocycloalkyl ring system may include, in addition to the nitrogen atom to which both R3 and R4 are attached, 1-3 other heteroatoms that are each independently O, S, or N; (ACT6051WOPCT1) each R5 and each R6 is independently H, C1-C6alkyl, or C3-C5cycloalkyl; or an R5 and R6 attached to the same carbon atom, together with that carbon atom, may form a C3-C6cycloalkyl ring; or an R5 or R6, together with an R3 or R4 may form an optionally substituted 3- 12- membered heterocycloalkyl ring, an optionally substituted 5-12-membered bridged heterocycloalkyl ring, an optionally substituted 4-12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12-membered spiroheterocycloalkyl ring system; and L is -C(O)NH-, -NHC(O)-, or -NHC(O)NH, wherein when n is 1, L is -NHC(O)-. [0010] Pharmaceutical compositions comprising such compounds, and methods of using such compounds in treating conditions in which PDGFR signaling is implicated are also provided. [0011] Also provided are compounds of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in which PDGFR signaling is implicated in a subject in need thereof are also provided. [0012] The disclosure also provides the use of a compounds of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder in which PDGFR signaling is implicated in a subject in need thereof. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS [0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting of the disclosure. [0014] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise (such as in the case of a group containing a number of carbon atoms in which case each carbon atom number falling within the range is provided), between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of (ACT6051WOPCT1) the limits, ranges excluding either both of those included limits are also included in the disclosure. [0015] The following terms are used to describe the present disclosure. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present disclosure. [0016] The articles “a” and “an” as used herein and in the appended claims are used herein to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, “an element” means one element or more than one element. [0017] The term “compound”, as used herein, unless otherwise indicated, refers to any specific chemical compound disclosed herein and includes tautomers, optical isomers (enantiomers) and other stereoisomers (diastereomers) thereof, as well as pharmaceutically acceptable salts and derivatives, including prodrug and/or deuterated forms thereof where applicable. Deuterated small molecules contemplated are those in which one or more of the hydrogen atoms contained in the drug molecule have been replaced by deuterium. It is understood by those of ordinary skill that molecules which are described herein are stable compounds as generally described hereunder. [0018] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, e.g., in humans. [0019] “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- (ACT6051WOPCT1) hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. [0020] A “pharmaceutically acceptable excipient” refers to a substance that is non- toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. [0021] A “solvate” refers to a physical association of a compound of formula (I) with one or more solvent molecules. [0022] The term “alkyl,” when used alone or as part of a substituent group, refers to a straight- or branched-chain hydrocarbon group having from 1 to 12 carbon atoms (“C1- C12”), preferably 1 to 6 carbons atoms (“C1-C6”), in the group. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like. In some embodiments, the alkyl group is a C1-C6 alkyl; in some embodiments, it is a C1-C4 alkyl. [0023] When a range of carbon atoms is used herein, for example, C1-C6, all ranges, as well as individual numbers of carbon atoms are encompassed. For example, “C1-C3” includes C1-C3, C1-C2, C2-C3, C1, C2, and C3. [0024] The term “cycloalkyl” when used alone or as part of a substituent group refers to cyclic-containing, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms (“C3-C10”), preferably from 3 to 6 carbon atoms (“C3-C6”). Examples of cycloalkyl (ACT6051WOPCT1) groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.1.0]heptanyl, spiro[3.3]heptanyl, and spiro[3.4]octanyl. [0025] The term “fluoroalkyl” when used alone or as part of a substituent group refers to an alkyl group wherein one or more of the hydrogen atoms has been replaced with one or more fluorine atoms. Examples of fluoroalkyl groups include -CF3, CHF2, -CH2F and the like. [0026] The term “heterocycloalkyl” when used alone or as part of a substituent group refers to any three to twelve-membered monocyclic, saturated or partially unsaturated ring containing at least one heteroatom that is O, N or S. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Examples of heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and the like. [0027] The term “bridged heterocycloalkyl ring” refers to any 5 to 12 membered heterocycloalkyl ring system that contains at least one bridged ring. Examples of bridged heterocycloalkyl rings include azabicyclo[3.1.1]heptane, azabicyclo[3.1.1]heptane, azabicyclo[2.2.2]octane, azabicyclo[2.2.1]heptane, azabicyclo[2.1.1]hexane, azabicyclo[1.1.1]pentane, azabicyclo[1.1.1]pentane, 6-oxa-azabicyclo[3.1.1]heptane, 6- diazabicyclo[3.1.1]heptane, 3-thia-azabicyclo[3.1.1]heptane, and the like. [0028] The term “fused heterocycloalkyl ring system” refers to a heterocycloalkyl ring to which another ring is fused. The other ring that is fused to the heterocycle ring may be another heterocycloalkyl ring, a cycloalkyl ring, an aryl ring, or a heteroaryl ring. In some embodiments, the fused heterocycloalkyl ring system is a 4 to 12 membered fused heterocycloalkyl ring system. [0029] The term “spiroheterocycloalkyl ring system” refers to a heterocycloalkyl ring that is substituted with a spirocyclic ring. The spirocyclic ring can be a cycloalkyl ring of a heterocycloalkyl ring. In some embodiments, the spiroheterocycloalkyl ring system is a 5-12-membered spiroheterocycloalkyl ring system. [0030] The terms “halo” or “halogen”, by itself or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom. (ACT6051WOPCT1) [0031] The term “aryl” when used alone or as part of a substituent group also refers to a mono- or bicyclic- aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more of the carbon atoms in the ring is optionally substituted. The term “aryl” also includes a mono- or bicyclic- aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein two adjacent carbon atoms in the ring are optionally substituted such that said two adjacent carbon atoms and their respective substituents form a cycloalkyl or heterocycloalkyl ring. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3,4-tetrahydronaphthyl, and the like. [0032] The term “heteroaryl” when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic ring structure including carbon atoms as well as up to four heteroatoms that are each independently nitrogen, oxygen, or sulfur. Heteroaryl rings can include a total of 5, 6, 9, or 10 ring atoms. The heteroaryl moiety can be unsubstituted, or one or more of the carbon atoms in the ring can be substituted. Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3- b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole. [0033] The term “optionally substituted,” as used herein to describe a substituent defined herein, means that the substituent may, but is not required to be, substituted with one or more suitable functional groups or other substituents as provided herein. For example, a substituent may be optionally substituted with one or more of: halo (i.e., -F, -Cl, -Br, -I), cyano, -OH, -C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -C1- C6 alkoxy, -C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylamino, -NH2, -NH(C1-C6 alkyl), - N(C1-C-6 alkyl)2, -NH(C1-C6 alkoxy), -C(O)NHC1-C6 alkyl, -C(O)N(C1-C6 alkyl)2, -COOH, - C1-C6alkylCOOH, -C3-C6cycloalkylCOOH, -C(O)NH2, C1-C6alkylCONH2, -C3- C6cycloalkylCONH2, C1-C6alkylCONHC1-C6alkyl, C1-C6alkylCON(C1-C6alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -NHCO(C1-C6 alkyl), -N(C1-C6 alkyl)C(O)(C1-C6 alkyl), -S(O)C1- C6 alkyl, -S(O)2C1-C6 alkyl, oxo, 6-12 membered aryl, or 5 to 12 membered heteroaryl groups. [0034] In particular, a substituent may be optionally substituted with one or more of: halo (i.e., -F, -Cl, -Br, -I), cyano, -C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6 (ACT6051WOPCT1) alkynyl, C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 haloalkoxy, C1- C6 alkylthio, C1-C6 alkylamino, -NH2, -NH(C1-C6 alkyl), -N(C1-C-6 alkyl)2, -NH(C1-C6 alkoxy), -C(O)NHC1-C6 alkyl, -C(O)N(C1-C6 alkyl)2, -COOH, -C1-C6alkylCOOH, -C3- C6cycloalkylCOOH, -C(O)NH2, C1-C6alkylCONH2, -C3-C6cycloalkylCONH2, C1- C6alkylCONHC1-C6alkyl, C1-C6alkylCON(C1-C6alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -NHCO(C1-C6 alkyl), -N(C1-C6 alkyl)C(O)(C1-C6 alkyl), -S(O)C1-C6 alkyl, -S(O)2C1- C6 alkyl, oxo, 6-12 membered aryl, or 5 to 12 membered heteroaryl groups. In some embodiments, each of the above optional substituents are themselves optionally substituted by one or two groups. [0035] In other embodiments, a substituent may be optionally substituted with one or more of: halo (i.e., -F, -Cl, -Br, -I), cyano, -OH, -C1-C6alkyl, -CH2CH2OH, -CH2CH2F, - OCH2CH2F, -CH2CH2CH(OH)CH2(OH), -CH2CH(OH)CH2(OH), -CH2CH(OH)CH3, - CH2OH, -C (CH3)2CH2(OH), -CH2OCH3, -CH2CH2OCH3, -CH2-(C3-C6cycloalkyl), -C3- C6cycloalkyl, C2-C6alkenyl, C2-C6 alkynyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -OCH3, -C1-C6 haloalkoxy, -OCH2CH2F, -C1-C6 alkylthio, C1-C6 alkylamino, -NH2, -NH(C1-C6 alkyl), - N(C1-C-6 alkyl)2, -NH(C1-C6 alkoxy), -C(O)NHC1-C6 alkyl, -CH2C(O)NHC1-C6 alkyl, - C(O)N(C1-C6 alkyl)2, -COOH, -C1-C6alkylCOOH, -C3-C6cycloalkylCOOH, -C(O)NH2, -C1- C6alkylCONH2, -C1-C6alkyl-CN, -C3-C6cycloalkylCONH2, -C1-C6alkylCONHC1-C6alkyl, C1- C6alkylCON(C1-C6alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -NHCO(C1-C6 alkyl), - N(C1-C6 alkyl)C(O)(C1-C6 alkyl), -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -C1-C6 alkyl- S(O)2C1-C6 alkyl, oxo, a 4-7 membered heterocycloalkyl group, -CH2-(4-7 membered heterocycloalkyl), 6-12 membered aryl, 5 to 12 membered heteroaryl groups, -CH2-(5 to 12 membered heteroaryl)-O-CH2-(6-12 membered aryl), -CH2-(5 to 12 membered heteroaryl)- OH. In some embodiments, each of the above optional substituents are themselves optionally substituted by one or two groups. [0036] As used herein, the term “alkenyl” refers to a straight- or branched-chain group having from 2 to 12 carbon atoms (“C2-C12”), preferably 2 to 4 carbons atoms (“C2- C4”), in the group, wherein the group includes at least one carbon-carbon double bond. Examples of alkenyl groups include vinyl (-CH=CH2; C2alkenyl) allyl (-CH2- CH=CH2; C3alkenyl), propenyl (-CH=CHCH3; C3alkenyl); isopropenyl (-C(CH3)=CH2; C3alkenyl), butenyl (-CH=CHCH2CH3; C4alkenyl), sec-butenyl (-C(CH3)=CHCH3; C4alkenyl), iso- (ACT6051WOPCT1) butenyl (-CH=C(CH3)2; C4alkenyl), 2-butenyl (-CH2CH=CHCH3; C4alkyl), pentenyl (-CH=CHCH2CH2CH3; C5alkenyl), and the like. [0037] As used herein, the term “alkynyl” refers to a straight- or branched-chain group having from 1 to 12 carbon atoms (“C1-C12”), preferably 1 to 4 carbons atoms (“C2- C4”), in the group, and wherein the group includes at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl (-C≡CH; C2alkynyl); propargyl (-CH2-C≡CH; C3alkynyl), propynyl (-C≡CCH3; C3alkynyl); butynyl (-C≡CCH2CH3; C4alkynyl), pentynyl (-C≡CCH2CH2CH3; C5alkynyl), and the like. [0038] As used herein, the term “alkoxy” refers to an oxygen radical attached to an alkyl group by a single bond. Examples of alkoxy groups include methoxy (-OCH3), ethoxy (-OCH2CH3), isopropoxy (-OCH(CH3)2) and the like. [0039] As used herein, the term “haloalkoxy” refers to an oxygen radical attached to a haloalkyl group by a single bond. Examples of haloalkoxy groups include -OCF3, - OCH2CF3, -OCH(CF3)2, and the like. [0040] The term “haloalkyl” refers to an alkyl group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms. [0041] The term “haloalkoxy” refers to an alkoxy group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms. [0042] As used herein, the term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space, e.g., enantiomers, diastereomers or tautomers. [0043] The term “patient” or “subject” is used throughout the specification to describe an animal, preferably a human or a domesticated animal, to whom treatment, including prophylactic treatment, with the compositions according to the present disclosure is provided. For treatment of those conditions or disease states which are specific for a specific animal such as a human patient, the term patient refers to that specific animal, including a domesticated animal such as a dog or cat or a farm animal such as a horse, cow, sheep, etc. In general, in the present disclosure, the term patient refers to a human patient unless otherwise stated or implied from the context of the use of the term. [0044] The term “effective” is used to describe an amount of a compound, composition or component which, when used within the context of its intended use, effects an (ACT6051WOPCT1) intended result. The term effective subsumes all other effective amount or effective concentration terms, which are otherwise described or used in the present application. [0045] “Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (e.g., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder. [0046] It should be understood that references herein to methods of treatment using one or more compounds or formulations thereof (e.g. a compound of formula (I)) should also be interpreted as references to: • one or more compounds or formulations thereof (e.g. a compound of formula (I)) for use in methods of treatment; and/or • the use of one or more compounds or formulations thereof (e.g. a compound of formula (I)) in the manufacture of a medicament for treating a pathological condition. [0047] In some aspects, the disclosure is directed to a compound of formula (I):
Figure imgf000012_0001
or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted phenyl ring or an optionally substituted pyridinyl ring; R1 is optionally substituted C1-C6alkyl or optionally substituted C3-C5cycloalkyl; (ACT6051WOPCT1) R2 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted C1-C6-alkyl-cycloalkyl, optionally substituted C1-C6-alkyl, or optionally substituted heterocycloalkyl; n is 1, 2, or 3; R3 and R4 are each independently optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted spirocycloalkyl, or optionally substituted heterocycloalkyl; or one of R3 or R4 may be H; or R3 and R4 , together with the nitrogen atom to which they are both attached, form an optionally substituted 3-12-membered heterocycloalkyl ring, an optionally substituted 5- 12-membered bridged heterocycloalkyl ring, an optionally substituted 4- 12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12- membered spiroheterocycloalkyl ring system, wherein said 3-12-membered heterocycloalkyl ring, 5-12- membered bridged heterocycloalkyl ring, 4-12-membered fused heterocycloalkyl ring system, or 5-12-membered spiroheterocycloalkyl ring system may include, in addition to the nitrogen atom to which both R3 and R4 are attached, 1-3 other heteroatoms that are each independently O, S, or N; each R5 and each R6 is independently H, C1-C6alkyl, or C3-C5cycloalkyl; or an R5 and R6 attached to the same carbon atom, together with that carbon atom, may form a C3-C6cycloalkyl ring; or an R5 or R6, together with an R3 or R4 may form an optionally substituted 3-12- membered heterocycloalkyl ring, an optionally substituted 5-12-membered bridged heterocycloalkyl ring, an optionally substituted 4-12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12-membered spiroheterocycloalkyl ring system; and L is -C(O)NH-, -NHC(O)-, or -NHC(O)NH, wherein when n is 1, L is -NHC(O)-. [0048] In some embodiments, A is an optionally substituted phenyl ring. [0049] In some embodiments, A is an optionally substituted pyridinyl ring. [0050] In some aspects, R1 in the compounds of formula (I) is optionally substituted C1-C6alkyl or optionally substituted C3-C5cycloalkyl. (ACT6051WOPCT1) [0051] In some embodiments, R1 is optionally substituted C1-C6alkyl, such as, for example, optionally substituted: C6alkyl, C5alkyl, C4alkyl, C3alkyl, C2alkyl, C1alkyl, methyl, ethyl, and the like. In some embodiments, the optionally substituted C1-C6alkyl is substituted C1-C6alkyl. In other embodiments, the optionally substituted C1-C6alkyl is unsubstituted C1- C6alkyl. [0052] In some embodiments, R1 is methyl. [0053] In other embodiments, R1 is optionally substituted C3-C5cycloalkyl, such as, for example, optionally substituted: C5cycloalkyl, C4cycloalkyl, C3cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, and the like. [0054] In some aspects, R2 in the compounds of formula (I) is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted C1-C6-alkyl-cycloalkyl, optionally substituted C1-C6-alkyl, or optionally substituted heterocycloalkyl. [0055] In some embodiments, R2 is optionally substituted aryl. [0056] In some embodiments, R2 is optionally substituted heteroaryl. [0057] In some embodiments, R2 is unsubstituted heteroaryl, such as, for example, pyrazinyl, pyrimidinyl, oxazolyl, or pyridinyl. [0058] In some embodiments, R2 is pyrazinyl. [0059] In some embodiments, R2 is pyrimidin-5-yl or pyrimidin-4-yl. [0060] In some embodiments, R2 is oxazol-5-yl. [0061] In some embodiments, R2 is pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl. [0062] In some embodiments, R2 is substituted heteroaryl, such as, for example, substituted pyrazolyl, substituted imidazolyl, substituted triazolyl, substituted furanyl, substituted thiophenyl, substituted pyrimidinyl, or substituted pyridinyl. [0063] In some embodiments, R2 is substituted pyrazolyl. [0064] In some embodiments, R2 is 1-methylpyrazol-5-yl, 1-methylpyrazol-4-yl, 1,3-dimethylpyrazol-4-yl, 1-cyclopropylpyrazol-4-yl, 1-(2-methoxyethyl)-pyrazol-4-yl, 1-(2- hydroxyethyl)-pyrazol-4-yl, 5-(hydroxymethyl)-1-methylpyrazol-3-yl, 1-(2,3- dihydroxypropan-1-yl)-pyrazol-4-yl, 1-(acetamid-2-yl)-pyrazol-4-yl, or 1-(oxetan-3-yl)- pyrazol-4-yl. [0065] In some embodiments, R2 is 1-methylpyrazol-5-yl. [0066] In some embodiments, R2 is 1-methylpyrazol-4-yl. (ACT6051WOPCT1) [0067] In some embodiments, R2 is 1,3-dimethylpyrazol-4-yl. [0068] In some embodiments, R2 is 1-cyclopropylpyrazol-4-yl. [0069] In some embodiments, R2 is 1-(2-methoxyethyl)-pyrazol-4-yl. [0070] In some embodiments, R2 is 1-(2-hydroxyethyl)-pyrazol-4-yl. [0071] In some embodiments, R2 is 5-(hydroxymethyl)-1-methylpyrazol-3-yl. [0072] In some embodiments, R2 is 1-(2,3-dihydroxypropan-1-yl)-pyrazol-4-yl. [0073] In some embodiments, R2 is 1-(acetamid-2-yl)-pyrazol-4-yl. [0074] In some embodiments, R2 is 1-(oxetan-3-yl)-pyrazol-4-yl. [0075] In some embodiments, R2 is substituted imidazolyl. [0076] In some embodiments, R2 is 1-methylimidazol-4-yl, or 5-(hydroxymethyl)-1- methylimidazol-2-yl. [0077] In some embodiments, R2 is 1-methylimidazol-4-yl. [0078] In some embodiments, R2 is 5-(hydroxymethyl)-1-methylimidazol-2-yl. [0079] In some embodiments, R2 is substituted triazolyl. [0080] In some embodiments, R2 is 1-methyl-1,2,3-triazol-4-yl. [0081] In some embodiments, R2 is substituted furanyl. [0082] In some embodiments, R2 is 2-(hydroxymethyl)furan-5-yl. [0083] In some embodiments, R2 is substituted thiophenyl. [0084] In some embodiments, R2 is 2-(hydroxymethyl)thiophen-5-yl. [0085] In some embodiments, R2 is substituted pyridinyl. [0086] In some embodiments, R2 is 2-(hydroxymethyl)pyridin-4-yl. [0087] In some embodiments, R2 is substituted pyrimidinyl. [0088] In some embodiments, R2 is optionally substituted cycloalkyl. [0089] In some embodiments, R2 is optionally substituted C1-C6-alkyl-cycloalkyl. [0090] In some embodiments, R2 is optionally substituted C1-C6-alkyl. [0091] In some embodiments, R2 is optionally substituted heterocycloalkyl. [0092] In some aspects, n in the compounds of formula (I) is 1, 2, or 3. [0093] In some embodiments, n is 1. [0094] In some embodiments, n is 2. [0095] In some embodiments, n is 3. [0096] In some aspects, R3 and R4 in the compounds of formula (I) are each independently optionally substituted aryl, optionally substituted heteroaryl, optionally (ACT6051WOPCT1) substituted alkyl, optionally substituted cycloalkyl, optionally substituted spirocycloalkyl, or optionally substituted heterocycloalkyl; or one of R3 or R4 may be H. [0097] In some embodiments, R3 or R4 is optionally substituted aryl. [0098] In some embodiments, R3 or R4 is optionally substituted heteroaryl. [0099] In some embodiments, R3 or R4 is optionally substituted alkyl. [00100] In some embodiments, R3 or R4 is methyl. [00101] In some embodiments, R3 or R4 is isopropyl. [00102] In some embodiments, R3 or R4 is optionally substituted cycloalkyl. [00103] In some embodiments, R3 or R4 is optionally substituted spirocycloalkyl. [00104] In some embodiments, R3 or R4 is optionally substituted heterocycloalkyl. [00105] In some embodiments R3 or R4 is tetrahydropyran-4-yl. [00106] In some embodiments, one of R3 or R4 in compounds of formula (I) is H. [00107] In some embodiments, R3 is optionally substituted C1-C6alkyl and R4 is optionally substituted heterocycloalkyl. [00108] In some embodiments, R3 is methyl and R4 is optionally substituted heterocycloalkyl. [00109] In some embodiments, R3 is methyl and R4 is tetrahydropyran-4-yl. [00110] In other aspects, R3 and R4 in the compounds of formula (I), together with the nitrogen atom to which they are both attached, form an optionally substituted 3-12- membered heterocycloalkyl ring, an optionally substituted 5-12-membered bridged heterocycloalkyl ring, an optionally substituted 4- 12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12- membered spiroheterocycloalkyl ring system, wherein said 3-12-membered heterocycloalkyl ring, 5-12-membered bridged heterocycloalkyl ring, 4-12-membered fused heterocycloalkyl ring system, or 5-12-membered spiroheterocycloalkyl ring system may include, in addition to the nitrogen atom to which both R3 and R4 are attached, 1-3 other heteroatoms that are each independently O, S, or N. [00111] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form an optionally substituted 3-12-membered heterocycloalkyl ring. [00112] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form an optionally substituted 4-6-membered heterocycloalkyl ring. [00113] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form an optionally substituted 3-12-membered heterocycloalkyl ring (ACT6051WOPCT1)
Figure imgf000017_0006
[00114] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a piperidinyl group,
Figure imgf000017_0001
. [00115] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a 2,2-dimethylpyrrolidin-1-yl group,
Figure imgf000017_0002
. [00116] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a 3,3-dimethylazetidin-1-yl group,
Figure imgf000017_0003
. [00117] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a 2,2-dimethylazetidin-1-yl group,
Figure imgf000017_0004
. [00118] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a 2-methyl-pyrrolidin-1-yl group,
Figure imgf000017_0005
. (ACT6051WOPCT1) [00119] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a (R)-2-methyl-pyrrolidin-1-yl group,
Figure imgf000018_0001
. [00120] In other embodiments, R3 and R4, together with the nitrogen atom to which
Figure imgf000018_0002
. [00121] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a 3-methyl-pyrrolidin-1-yl group,
Figure imgf000018_0003
. [00122] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a (R)-3-methyl-pyrrolidin-1-yl group. [00123] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a (S)-3-methyl-pyrrolidin-1-yl group,
Figure imgf000018_0004
. [00124] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form (R)-3-methyl-pyrrolidin-1-yl,
Figure imgf000018_0005
. [00125] In other embodiments, R3 and R4, together with the nitrogen atom to which
Figure imgf000018_0006
they are both attached, form a morpholin-4-yl, . [00126] In other embodiments, R3 and R4, together with the nitrogen atom to which
Figure imgf000018_0007
they are both attached, form 2-ethyl-morpholin-4-yl, . [00127] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form (S)-2-ethyl-morpholin-4-yl. (ACT6051WOPCT1) [00128] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form (R)-2-ethyl-morpholin-4-yl. [00129] In other embodiments, R3 and R4, together with the nitrogen atom to which
Figure imgf000019_0001
they are both attached, form 2-methyl-morpholin-4-yl,
Figure imgf000019_0002
. [00130] In other embodiments, R3 and R4, together with the nitrogen atom to which O (S) N they are both attached, form (S)-2-methyl-morpholin-4-yl,
Figure imgf000019_0003
. [00131] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form (R)-2-methyl-morpholin-4-yl. [00132] In other embodiments, R3 and R4, together with the nitrogen atom to which
Figure imgf000019_0004
they are both attached, form 3-methyl-morpholin-4-yl, . [00133] In other embodiments, R3 and R4, together with the nitrogen atom to which
Figure imgf000019_0005
they are both attached, form (R)-3-methyl-morpholin-4-yl,
Figure imgf000019_0006
. [00134] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form (S)-3-methyl-morpholin-4-yl. [00135] In other embodiments, R3 and R4, together with the nitrogen atom to which OMe N they are both attached, form . [00136] In other embodiments, R3 and R4, together with the nitrogen atom to which
Figure imgf000019_0007
they are both attached, form
Figure imgf000019_0008
. (ACT6051WOPCT1) [00137] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form 3,5-dimethyl-morpholin-4-yl,
Figure imgf000020_0001
. [00138] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form (3R,5R)-3,5-dimethyl-morpholin-4-yl,
Figure imgf000020_0002
. [00139] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form (3S,5R)-3,5-dimethyl-morpholin-4-yl. [00140] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form 2,6-dimethyl-morpholin-4-yl,
Figure imgf000020_0003
. [00141] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form (2R,6R)-2,6-dimethyl-morpholin-4-yl. [00142] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form (2S,6R)-2,6-dimethyl-morpholin-4-yl. [00143] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form
Figure imgf000020_0004
. [00144] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form an optionally substituted 5-12-membered bridged heterocycloalkyl ring. [00145] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form an optionally substituted 8-membered bridged heterocycloalkyl ring. [00146] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a 2-azabicyclo[2.2.2]octanyl group,
Figure imgf000020_0005
. ĨACT6051WOPCT1) [00147] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form an 3-oxa-8-azabicyclo[3.2.1]octan-8-yl group,
Figure imgf000021_0001
. [00148] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form
Figure imgf000021_0002
. [00149] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form an optionally substituted 4-12-membered fused heterocycloalkyl ring system. [00150] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form an optionally substituted 6-7-membered fused heterocycloalkyl ring system. [00151] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a 3-azabicyclo[3.2.0]heptanyl group:
Figure imgf000021_0003
. [00152] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a 3-azabicyclo[3.1.0]hexanyl group:
Figure imgf000021_0004
. [00153] In other embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form
Figure imgf000021_0005
. [00154] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form an optionally substituted 5-12-membered spiroheterocycloalkyl ring system. [00155] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form an optionally substituted 7-9-membered spiroheterocycloalkyl ring. ĨACT6051WOPCT1) [00156] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a 4-azaspiro[2.4]heptan-4-yl group,
Figure imgf000022_0001
. [00157] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a 5-azaspiro[2.4]heptan-5-yl group,
Figure imgf000022_0002
. [00158] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a 5-azaspiro[3.4]octan-5-yl group,
Figure imgf000022_0003
. [00159] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a 6-azaspiro[3.4]octan-6-yl group,
Figure imgf000022_0004
. [00160] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a 2-oxa-5-azaspiro[3.4]octan-5-yl group,
Figure imgf000022_0005
. [00161] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a 1-oxa-7-azaspiro[3.5]nonan-7-yl group,
Figure imgf000022_0006
. (ACT6051WOPCT1) [00162] In some embodiments, R3 and R4, together with the nitrogen atom to which they are both attached, form a 8-oxa-5-azaspiro[3.5]nonan-5-yl group,
Figure imgf000023_0001
. [00163] In some aspects, each R5 and each R6 is independently H, C1-C6alkyl, or C3-C5cycloalkyl. [00164] In some embodiments, an R5 or an R6 is H. [00165] In some embodiments, an R5 or an R6 is C1-C6alkyl, such as, for example, C6alkyl, C5alkyl, C4alkyl, C3alkyl, C2alkyl, C1alkyl, methyl, ethyl, and the like. [00166] In some embodiments, an R5 or an R6 is C3-C5cycloalkyl, such as, for example, C5cycloalkyl, C4cycloalkyl, C3cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, and the like. [00167] In some embodiments, each R5 and each R6 is H. [00168] In some aspects, an R5 or R6 in the compounds of formula (I), together with an R3 or R4 form an optionally substituted 3-12-membered heterocycloalkyl ring, an optionally substituted 5-12-membered bridged heterocycloalkyl ring, an optionally substituted 4-12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12-membered spiroheterocycloalkyl ring system. [00169] In some embodiments an R5 or R6, together with an R3 or R4 form an optionally substituted 4- or 5-membered heterocycloalkyl ring, such as, for example, an optionally substituted azetidnyl ring, or an optionally substituted pyrrolidinyl ring. [00170] In some embodiments of the compounds of formula (I), an R5 or R6, together with an R3 or R4 form an optionally substituted 3-12-membered heterocycloalkyl ring. [00171] In some embodiments of the compounds of formula (I) wherein an R5 or R6, together with an R3 or R4 may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure
Figure imgf000023_0002
formula (I) is (ACT6051WOPCT1)
Figure imgf000024_0001
[00172] In other embodiments of the compounds of formula (I) wherein an R5 or R6, together with an R3 or R4 may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure
Figure imgf000024_0002
formula (I) is
Figure imgf000024_0003
[00173] In other embodiments of the compounds of formula (I) wherein an R5 or R6, together with an R3 or R4 may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure
Figure imgf000024_0004
formula (I) is
Figure imgf000024_0005
[00174] In some aspects, L is -C(O)NH-, -NHC(O)-, or -NHC(O)NH, wherein when n is 1, L is -NHC(O)-. [00175] In some embodiments, L is -NHC(O)-. [00176] In other embodiments, L is -C(O)NH-. [00177] In other embodiments, L is -NHC(O)NH-. [00178] The diradicals “-L-,” as used herein, are written from left-to-right such that the left hand side of L is attached to the pyridinyl moiety in the compounds of the disclosure. [00179] In some embodiments of the compounds of formula (I), n is 1 and L is - NHC(O)-. [00180] In some embodiments of the compounds of formula (I), n is 2 and L is - NHC(O)-. (ACT6051WOPCT1) [00181] In some embodiments of the compounds of formula (I), n is 2 and L is - C(O)NH-. [00182] In some embodiments of the compounds of formula (I), n is 2 and L is - NHC(O)NH-. [00183] In some embodiments, the compound of formula (I) is a compound of formula (IA):
Figure imgf000025_0001
or a pharmaceutically acceptable salt thereof, wherein Q is N or CH; R7 is H, C1-C6alkyl, C3-C6cycloalkyl, halogen, -CN, or C1-C4fluoroalkyl; and R8 is H, C1-C6alkyl, C3-C6cycloalkyl, halogen, or C1-C4fluoroalkyl, and the other variables are as described above for the compound of formula (I). [00184] In some embodiments of the compound of formula (IA), Q is N. [00185] In other embodiments of the compound of formula (IA), Q is CH. [00186] In some embodiments of the compound of formula (IA), R7 is H. [00187] In other embodiments of the compound of formula (IA), R7 is C1-C6alkyl. [00188] In other embodiments of the compound of formula (IA), R7 is C3- C6cycloalkyl. [00189] In other embodiments of the compound of formula (IA), R7 is halogen, such as, for example, -F, -Cl, -Br, or -I. [00190] In other embodiments of the compound of formula (IA), R7 is -CN. [00191] In other embodiments of the compound of formula (IA), R7 is C1- C4fluoroalkyl. [00192] In some embodiments of the compound of formula (IA), R8 is H. (ACT6051WOPCT1) [00193] In other embodiments of the compound of formula (IA), R8 is C1-C6alkyl. [00194] In other embodiments of the compound of formula (IA), R8 is C3- C6cycloalkyl. [00195] In other embodiments of the compound of formula (IA), R8 is halogen, such as, for example, -F, -Cl, -Br, or -I. [00196] In other embodiments of the compound of formula (IA), R8 is C1- C4fluoroalkyl. [00197] In some aspects, the compound of formula (IA) is a compound of formula (IA-1):
Figure imgf000026_0001
[00198] In some aspects, the compound of formula (IA) is a compound of formula (IA-2):
Figure imgf000026_0002
wherein R7 is -CH3 or -F. [00199] In some aspects, the compound of formula (I) is: N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(pyridin-3-yl)-1H- pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(2- methylmorpholino)ethyl)nicotinamide; (ACT6051WOPCT1) N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; 6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-(pyrrolidin-1-yl)ethyl)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(2-methylpyrrolidin-1- yl)ethyl)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-(2-methylpyrrolidin-1-yl)ethyl)nicotinamide; N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(pyridin-4-yl)-1H- pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; 6-methyl-5-((1-methyl-8-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)-N-(2-(pyrrolidin-1-yl)ethyl)nicotinamide; rac-N-(2-((2R,6R)-2,6-dimethylmorpholino)ethyl)-6-methyl-5-((1-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)nicotinamide; N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-5-((8-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)- 1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-6- methylnicotinamide; rac-N-(2-((2R,6R)-2,6-dimethylmorpholino)ethyl)-6-methyl-5-((1-methyl-8-(pyridin- 3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; 5-((8-(1-(2-amino-2-oxoethyl)-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6- methylnicotinamide; 5-((8-(1-(2,3-dihydroxypropyl)-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6- methylnicotinamide; N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- imidazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; (ACT6051WOPCT1) 6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-morpholinoethyl)nicotinamide; N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(pyrimidin-4-yl)- 1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; N-(2-((3R,5R)-3,5-dimethylmorpholino)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)nicotinamide; 6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)- yl)ethyl)nicotinamide; 6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-(piperidin-1-yl)ethyl)nicotinamide; N-(2-(5-azaspiro[2.4]heptan-5-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; N-(2-(3,3-dimethylazetidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; N-(2-(2,2-dimethylmorpholino)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-5-((8-(5-(hydroxymethyl)-1-methyl-1H- pyrazol-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-6- methylnicotinamide; 6-methyl-N-(2-(methyl(tetrahydro-2H-pyran-4-yl)amino)ethyl)-5-((1-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)nicotinamide; (S)-5-((8-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-6-methyl-N-(2-(2-methylpyrrolidin-1- yl)ethyl)nicotinamide; (ACT6051WOPCT1) (S)-5-((8-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-6-methyl-N-(2-(2-methylpyrrolidin-1- yl)ethyl)nicotinamide; (R)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(2-methylpyrrolidin-1- yl)ethyl)nicotinamide; N-(2-(4-methoxypiperidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; N-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)nicotinamide; N-(2-(8-oxa-5-azaspiro[3.5]nonan-5-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(2-methylpyrrolidin-1- yl)ethyl)nicotinamide; N-(2-(2-oxa-5-azaspiro[3.4]octan-5-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; (S)-5-((8-(5-(hydroxymethyl)thiophen-2-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-6-methyl-N-(2-(2-methylpyrrolidin-1-yl)ethyl)nicotinamide; (S)-5-((8-(5-(hydroxymethyl)furan-2-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-6-methyl-N-(2-(2-methylpyrrolidin-1-yl)ethyl)nicotinamide; (R)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(3-methylpyrrolidin-1- yl)ethyl)nicotinamide; (S)-5-((8-(2-(hydroxymethyl)pyridin-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-6-methyl-N-(2-(2-methylpyrrolidin-1-yl)ethyl)nicotinamide; (ACT6051WOPCT1) (R)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(3- methylmorpholino)ethyl)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-(2-methylpyrrolidin-1-yl)ethyl)nicotinamide; N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-5-((8-(2-(hydroxymethyl)pyridin-4-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-6- methylnicotinamide; N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- 1,2,3-triazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)nicotinamide; N-(2-(2-ethylmorpholino)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4- yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(3-methylpyrrolidin-1- yl)ethyl)nicotinamide; 6-methyl-5-((1-methyl-8-(pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)-N-(2-morpholinoethyl)nicotinamide; 6-methyl-5-((1-methyl-8-(1-methyl-1H-imidazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-morpholinoethyl)nicotinamide; 6-methyl-5-((1-methyl-8-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)-N-(2-morpholinoethyl)nicotinamide; (S)-5-((8-(5-(hydroxymethyl)-1-methyl-1H-imidazol-2-yl)-1-methyl-1H- pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-6-methyl-N-(2-(2- methylpyrrolidin-1-yl)ethyl)nicotinamide; 5-((8-(1-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-6-methyl-N-(2-morpholinoethyl)nicotinamide; 5-((8-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-6-methyl-N-(2-morpholinoethyl)nicotinamide; (ACT6051WOPCT1) 5-((8-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-6-methyl-N-(2-morpholinoethyl)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-(2-methylpyrrolidin-1-yl)ethyl)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(pyrazin-2-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-(2-methylpyrrolidin-1-yl)ethyl)nicotinamide; 6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-morpholinoethyl)nicotinamide; (S)-N-((1-isopropylpyrrolidin-2-yl)methyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; (R)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-((1-methylazetidin-2- yl)methyl)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-((1-methylazetidin-2- yl)methyl)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-((1-methylpyrrolidin-2- yl)methyl)nicotinamide; (R)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-((1-methylpyrrolidin-2- yl)methyl)nicotinamide; or (R)-N-((1-isopropylpyrrolidin-2-yl)methyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; or a pharmaceutically acceptable salt of any of the compounds listed above. [00200] In some aspects, the compounds according to formula (I) are those that have an IC50 <20 nM in a PDGFR cellular assay such as, for example, that described in the Experimental section below. (ACT6051WOPCT1) [00201] In some embodiments, the compounds according to formula (I) are those that have an IC50 <5 nM in a PDGFR cellular assay such as, for example, that described in the Experimental section below. [00202] In some embodiments, the compound of the disclosure is one of Examples 1-58 described herein, or a pharmaceutically acceptable salt thereof. [00203] Stereoisomers of compounds of formula (I) are also contemplated by the present disclosure. Thus, the disclosure encompasses all stereoisomers and constitutional isomers of any compound disclosed or claimed herein, including all enantiomers and diastereomers. [00204] Pharmaceutically acceptable salts and solvates of the compounds of formula (I) are also within the scope of the disclosure. [00205] Isotopic variants of the compounds of formula (I) are also contemplated by the present disclosure. [00206] References to compounds of formula (I) herein, include the compounds of formula (I) and subgenera thereof (e.g., formula (IA), formula (IA-1), formula (IA-2)) disclosed herein. Pharmaceutical compositions and methods of administration [00207] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In some embodiments, the pharmaceutical compositions contain a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. [00208] The subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the one or more compounds of the invention and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time. (ACT6051WOPCT1) [00209] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above) w/w, w/v or v/v. [00210] In some embodiments, the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25% , 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above) w/w, w/v, or v/v. [00211] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to (ACT6051WOPCT1) approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v. [00212] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v. [00213] In some embodiments, the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g (or a number in the range defined by and including any two numbers above). [00214] In some embodiments, the amount of one or more compounds of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, , 0.15 g, 0.2 g, , 0.25 g, 0.3 g, , 0.35 g, 0.4 g, , 0.45 g, 0.5 g, 0.55 g, 0.6 g, , 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or a number in the range defined by and including any two numbers above). [00215] In some embodiments, the amount of one or more compounds of the invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g. [00216] In some embodiments, the compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per (ACT6051WOPCT1) day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. [00217] Unless otherwise noted, the amounts of the compounds described herein are set forth on a free base basis. That is, the amounts indicate that amount of the compound administered, exclusive of, for example, solvent (such as in solvates) or counterions (such as in pharmaceutically acceptable salts). [00218] Described below are non- limiting exemplary pharmaceutical compositions and methods for preparing the same. Pharmaceutical compositions for oral administration. [00219] In some embodiments, the invention provides a pharmaceutical composition for oral administration containing a compound of the invention, and a pharmaceutical excipient suitable for oral administration. [00220] In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) an effective amount of a third agent. [00221] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in- water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally (ACT6051WOPCT1) with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. [00222] This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf- life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs. [00223] An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include (ACT6051WOPCT1) powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. [00224] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof. [00225] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. [00226] Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof. [00227] Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other (ACT6051WOPCT1) glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition. [00228] When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof. [00229] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. [00230] Surfactant which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed. [00231] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (" HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. (ACT6051WOPCT1) [00232] Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions. [00233] Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di- glycerides; and mixtures thereof. [00234] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof. [00235] Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP -phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof. ĨACT6051WOPCT1) [00236] Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide. [00237] Other hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG- 100 succinate, PEG-24 cholesterol, polyglyceryl-lOoleate, Tween 40, Tween 60, sucrose monostearate, sucrose mono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers. (ACT6051WOPCT1) [00238] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides. [00239] In one embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion. [00240] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG ; amides and other nitrogen-containing compounds such as 2- pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone (ACT6051WOPCT1) and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water. [00241] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N- methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol. [00242] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%o, 50%), 100%o, or up to about 200%> by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%>, 2%>, 1%) or even less. Typically, the solubilizer may be present in an amount of about 1%> to about 100%, more typically about 5%> to about 25%> by weight. [00243] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. [00244] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, (ACT6051WOPCT1) ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para- bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium. [00245] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like. Pharmaceutical compositions for injection. [00246] In some embodiments, the invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein. [00247] The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. (ACT6051WOPCT1) [00248] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. [00249] Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. [00250] Pharmaceutical compositions for topical (e.g. transdermal) delivery. [00251] In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery containing a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery. [00252] Compositions of the present invention can be formulated into preparations in solid, semisolid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area. [00253] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability (ACT6051WOPCT1) barrier of the skin. There are many of these penetration- enhancing molecules known to those trained in the art of topical formulation. [00254] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. [00255] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, either with or without another agent. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos.5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Pharmaceutical compositions for inhalation. [00256] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. [00257] Compositions for inhalation may be delivered as a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant. Such devices are referred to in, for example, WO2013030802. (ACT6051WOPCT1) [00258] Where the inhalable form of the active ingredient is an aerosol composition, the inhalation device may be an aerosol vial provided with a valve adapted to deliver a metered dose, i.e. a metered dose inhaler. Where the inhalable form of the active ingredient is a nebulizable aqueous, organic or aqueous/organic dispersion, the inhalation device may be a nebulizer, such as an airjet nebulizer, or an ultrasonic nebulizer, or a hand- held nebulizer, sometimes referred to as a soft mist or soft spray inhaler, or a mechanical device which allows much smaller nebulized volumes than conventional nebulizers. Such devices are referred to in, for example, WO2013030802. [00259] Where the inhalable form of the active ingredient is the finely divided particulate form, the inhalation device may be, for example, a dry powder inhalation device adapted to deliver dry powder from a capsule or blister containing a dry powder comprising a dosage unit or a multidose dry powder inhalation (MDPI) device adapted to deliver dry powder comprising a dosage unit upon actuation. The dry powder composition preferably contains a diluent or carrier, such as lactose, and a compound that helps to protect against product performance deterioration due to moisture e.g. magnesium stearate. Dry powder inhalation devices are referred to in, for example, WO2013030802 [00260] Thus, in some embodiments, the invention also includes (A) a compound of the invention, or a pharmaceutically acceptable salt thereof, in inhalable form; (B) an inhalable medicament comprising the compound in inhalable form together with a pharmaceutically acceptable carrier in inhalable form; (C) a pharmaceutical product comprising such a compound in inhalable form in association with an inhalation device; and (D) an inhalation device containing such a compound in inhalable form. Other pharmaceutical compositions. [00261] Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., (ACT6051WOPCT1) The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001 ; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety. [00262] Administration of the compounds or pharmaceutical composition of the present invention can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally. [00263] The amount of the compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. by dividing such larger doses into several small doses for administration throughout the day. [00264] In some embodiments, a compound of the invention is administered in a single dose. [00265] Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes may be used as appropriate. A single dose of a compound of the invention may also be used for treatment of an acute condition. [00266] In some embodiments, a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once per day to about 6 times per (ACT6051WOPCT1) day. In another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary. [00267] Administration of the compounds of the invention may continue as long as necessary. In some embodiments, a compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects. [00268] An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra- arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant. [00269] The compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty. Without being bound by theory, compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis. A compound of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent. In some embodiments, a compound of the invention is admixed with a matrix. Such a matrix may be a polymeric matrix, and may serve to bond the compound to the stent. Polymeric matrices suitable for such use, include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g. polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds. Compounds of the ĨACT6051WOPCT1) invention may be applied to the surface of the stent by various methods such as dip/spin coating, spray coating, dip-coating, and/or brush-coating. The compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent. Alternatively, the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall. Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash. In yet other embodiments, compounds of the invention may be covalently linked to a stent or graft. A covalent linker may be used which degrades in vivo, leading to the release of the compound of the invention. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages. Compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis. [00270] A variety of stent devices which may be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U.S. Pat. No.5451233; U.S. Pat. No.5040548; U.S. Pat. No.5061273; U.S. Pat. No. 5496346; U.S. Pat. No.5292331; U.S. Pat. No.5674278; U.S. Pat. No.3657744; U.S. Pat. No.4739762; U.S. Pat. No.5195984; U.S. Pat. No.5292331 ; U.S. Pat. No.5674278; U.S. Pat. No.5879382; U.S. Pat. No.6344053. [00271] The compounds of the invention may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation in light of the instant disclosure. [00272] When a compound of the invention is administered in a composition that comprises one or more agents, and the agent has a shorter half- life than the compound of the invention unit dose forms of the agent and the compound of the invention may be adjusted accordingly. [00273] The subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release (ACT6051WOPCT1) formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc. [00274] Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired. Methods of Use [00275] The method typically comprises administering to a subject a therapeutically effective amount of a compound of the invention. The therapeutically effective amount of the subject combination of compounds may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downregulation of activity of a target protein. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. [00276] The disclosure also relates to methods of using the compounds described herein to treat in a subject in need thereof, a disease or disorder in which PDGFR signaling is implicated. These methods are accomplished by administering to the subject a compound of the disclosure in an amount effective to treat the disease or disorder. [00277] In some aspects, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is pulmonary hypertension (PH). [00278] In some embodiments, the pulmonary hypertension is pulmonary arterial hypertension (PAH) (WHO PH Group 1); PH secondary to heart failure (WHO PH Group 2); PH secondary to lung diseases and/or hypoxia (WHO PH Group 3); PH due to pulmonary (ACT6051WOPCT1) artery obstruction (WHO Group 4); or PH due to unknown or rare diseases (WHO PH Group 5). [00279] In some embodiments, the PAH (WHO PH Group 1) is idiopathic PAH, PAH with vasoreactivity, heritable PAH, drugs and toxins-induced PAH, PAH associated with connective tissue disease, PAH associated with HIV infection, PAH associated with portal hypertension, PAH associated with congenital heart disease, PAH associated with schistosomiasis, PAH in long-term responders to calcium channel blockers, PAH with overt signs of venous/capillaries involvement; persistent PH of the Newborn syndrome; or systemic sclerosis-associated PAH (SSc-PAH). [00280] In some embodiments, the PAH secondary to heart failure (WHO PH Group 2) is PH due to heart failure with preserved ejection fraction, PH due to heart failure with reduced ejection fraction, valvular heart disease, or congenital post-capillary obstructive lesions. [00281] In some embodiments, the PH secondary to lung diseases and/or hypoxia (WHO PH Group 3) is PH due to obstructive lung disease, PH due to restrictive lung disease, PH due to other lung diseases with mixed restrictive/obstructive pattern, PH due to hypoxia without lung disease, PH due to developmental lung disorders. [00282] In some embodiments, the PH due to obstructive lung disease is PH due to chronic obstructive pulmonary disease (COPD). [00283] In some embodiments, the PH due to restrictive lung disease is PH due to interstitial lung diseases (ILDs). [00284] In some embodiments, the PH due to interstitial lung diseases (ILDs) is PH due to idiopathic pulmonary fibrosis (IPF). [00285] In some embodiments, the PH due to pulmonary artery obstruction (WHO Group 4) is chronic thromboembolic PH (CTEPH) or PH due to other pulmonaty artery obstructions. [00286] In some embodiments, the PH due to unknown or rare diseases (WHO PH Group 5) is PH due to hematologic disorders, PH due to systemic disorders, PH due to other disorders, or PH due to complex congenital heart disease. [00287] In some aspects, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is a respiratory disease. ĨACT6051WOPCT1) [00288] In some embodiments, the respiratory disease is asthma. [00289] In some aspects, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is a fibrotic disease. [00290] In some embodiments, the fibrotic disease is pulmonary fibrosis, cardiac fibrosis or liver fibrosis. [00291] In some embodiments, the fibrotic disease is pulmonary fibrosis. [00292] In some embodiments, the pulmonary fibrosis is an interstitial lung disease. [00293] In some embodiments, the interstitial lung disease is idiopathic pulmonary fibrosis. [00294] In some embodiments, the interstitial lung disease is rheumatoid arthritis- associated interstitial lung disease. [00295] In some embodiments, the interstitial lung disease is systemic sclerosis- associated interstitial lung disease. [00296] In some embodiments, the interstitial lung disease is connective tissue disease-associated interstitial lung disease. [00297] In some embodiments, the interstitial lung disease is nonspecific interstitial pneumonia. [00298] In some embodiments, the interstitial lung disease is unclassifiable interstitial lung disease. [00299] In some embodiments, the interstitial lung disease is hypersensitivity pneumonitis. [00300] In some embodiments, the interstitial lung disease is sarcoidosis. [00301] In some embodiments, the interstitial lung disease is non-idiopathic pulmonary fibrosis interstitial lung disease. [00302] In some aspects, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is a dermatological disease. [00303] In some embodiments, the dermatological disease or disorder is atopic dermatitis, scleroderma, or urticaria. (ACT6051WOPCT1) [00304] In some aspects, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is an inflammatory disease or disorder. [00305] In some embodiments, the inflammatory disease or disorder is allergic rhinitis, irritable bowel syndrome (IBS); or inflammatory bowel disease (IBD). [00306] In some aspects, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is an autoimmune disorder. [00307] In some aspects, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is a metabolic disease. [00308] In some aspects, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is vascular restenosis; age-related macular degeneration (AMD); irritable bowel syndrome (IBS); inflammatory bowel disease (IBD); obesity-cell related diseases; type I diabetes or type II diabetes. [00309] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is pulmonary arterial hypertension (PAH). [00310] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH secondary to heart failure (WHO PH Group 2). [00311] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH due to heart failure with preserved ejection fraction. [00312] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH due to heart failure with reduced ejection fraction. [00313] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is valvular heart disease. (ACT6051WOPCT1) [00314] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is congenital post-capillary obstructive lesions. [00315] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH secondary to lung diseases and/or hypoxia (WHO PH Group 3). [00316] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH due to pulmonary artery obstruction (WHO Group 4). [00317] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is chronic thromboembolic PH (CTEPH). [00318] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH due to unknown or rare diseases (WHO PH Group 5). [00319] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is idiopathic PAH. [00320] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PAH associated with connective tissue disease. [00321] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is systemic sclerosis-associated PAH (SSc-PAH). [00322] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH secondary to interstitial lung diseases (ILDs). [00323] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH secondary to chronic obstructive pulmonary disease (COPD). (ACT6051WOPCT1) [00324] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH secondary to idiopathic pulmonary fibrosis (IPF). [00325] In treatment methods according to the disclosure, an effective amount of a pharmaceutical agent according to the disclosure is administered to a subject suffering from or diagnosed as having such a disease or disorder. An "effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic benefit in patients in need of such treatment for the designated disease or disorder. Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease or disorder, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day. [00326] In addition, the compounds of the disclosure may be used in combination with additional active ingredients in the treatment of the above diseases or disorders. The additional active ingredients may be coadministered separately with a compound of the disclosure or included with such an agent in a pharmaceutical composition according to the disclosure. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the disclosure), decrease one or more side effects, or decrease the required dose of the active agent according to the disclosure. [00327] It should be understood that references herein to methods of treatment using one or more compounds or formulations thereof should also be interpreted as references to: (i) one or more compounds or formulations thereof for use in methods of treatment; and/or (ii) the use of one or more compounds or formulations thereof in the manufacture of a medicament for treating a pathological condition. (ACT6051WOPCT1) [00328] Compounds of formula (I) in the present invention can be synthesized in accordance with general synthetic methods familiar to those who are skilled in the art. The following reaction schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention. Scheme 1
Figure imgf000056_0001
[00329] Scheme 1 illustrated the synthesis of Formula I. The acid (I-1) was first coupled with an amine (I-2), a couple agent such as HATU, a base such as TEA in a solvent such as DMF to give compound (I-3). The cyano containing compound (I-4) treated with alkylhydrazine (I-5) in a solvent with a base such as sodium carbonate an amine compound (I-6) which then treated with boronated agent (I-7), a catalyst such as PdCl2(dppf).CH2Cl2, a base such as Cs2CO3 and a solvent such as dioxane-water to yield compound (I-8). The amine (I-8) was then coupled with compound (I-3), a couple agent such as Brettphos-Pd-G3, a ligand such as Brettphos, a base such as Cs2CO3 in a solvent such as DMF to give Formula I. Alternatively, the amine (I-8) treated with compound (I-1), a couple agent such as Brettphos- Pd-G3, a ligand such as Brettphos, a base such as Cs2CO3 in a solvent such as DMF to yield (ACT6051WOPCT1) compound (I-8), compound (I-8) was then coupled with an amine (I-2), a couple agent such as HATU, a base such as TEA in a solvent such as DMF to give Formula I. Examples Example 1, N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(pyridin-3- yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide
Figure imgf000057_0001
Step a: 2-(2, 2-dimethylpyrrolidin-1-yl)acetonitrile
Figure imgf000057_0002
To a solution of 2,2-dimethylpyrrolidine (20 g, 201 mmol) and potassium carbonate (55.74 g, 403 mmol) in DMF (130 mL) was added 2-bromoacetonitrile (15.4 mL, 221 mmol) at room-temperature. The resulting mixture was stirred at 30 °C for 12 h. The reaction was concentrated under reduced pressure to give crude product, which was purified by column chromatography over silica gel (eluent: ethyl acetate: methanol = 7:3) to give the title compound 2-(2, 2-dimethylpyrrolidin-1-yl)acetonitrile (22 g, 79%) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 3.50 (s, 2H), 2.81 - 2.86 (m, 2H), 1.69 - 1.77 (m, 2H), 1.56 - 1.62 (m, 2H), 0.98 (s, 6 H). Step b: 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine
Figure imgf000057_0003
solution of 2-(2, 2-dimethylpyrrolidin-1-yl)acetonitrile (22 g, 159.18 mmol) in THF (400 mL) was added lithium aluminium hydride (7.25 g, 191.01 mmol) by portions at 0 °C (ice/water).The resultant mixture was stirred at 20 °C for 4 hours before quenched with water (7.25 g) at 0 °C. The reaction mixture was filtered. And the filtration was concentrated to dryness under reduced pressure to afford the crude product 2-(2, 2- dimethylpyrrolidin-1-yl)ethanamine a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 2.71 - 2.81 (m, 2H), 2.63 - 2.71 (m, 2H), 2.44 - 2.50 (m, 2H), 1.71 - 1.82 (m, 2H), 1.59 - 1.69 (m, 2H), 0.96 - 1.02 (m, 6H). Step c.5-bromo-N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6-methylnicotinamide (ACT6051WOPCT1)
Figure imgf000058_0001
[00332] A solution of 5-bromo-6-methylnicotinic acid (575 mg, 2.66 mmol) and 2- (3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1822 mg, 4.79 mmol) in DMF (10 mL) was stirred at room temperature for 15 minutes. Then 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (567 mg, 3.99 mmol) and triethylamine (1.39 mL, 7.99 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (10 mL), extracted with EtOAc (40 mL*3). The combined organic layers were washed with saturated aq NH4Cl (40 mL) and brine (40 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude title compound as pale brown oil. The crude was purified by flash column chromatography over a 4 g silica gel (gradient: DCM: CH3OH from 100:0 to 96:4). The desired fractions were collected, and the solvent was concentrated under vacuum to give title compound as a pale brown solid (900 mg, 99.4%). LCMS (ESI): mass calcd. for C15H22BrN3O, 340.3; m/z found, 342.1 [M+H]+.1H NMR (400MHz, CHLOROFORM-d) δ = 8.79 (d, J=1.9 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.86 (br t, J=5.2 Hz, 1H), 4.10 - 3.92 (m, 1H), 3.82 - 3.66 (m, 2H), 3.51 - 3.39 (m, 1H), 3.20 (qd, J=8.4, 11.8 Hz, 2H), 2.62 (s, 3H), 2.19 - 2.09 (m, 2H), 2.05 - 1.96 (m, 2H), 1.39 (s, 3H), 1.23 (s, 3H) Step d.8-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine
Figure imgf000058_0002
[00333] To a solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carbonitrile (650 mg, 2.53 mmol) in DMF (13 mL) were added methylhydrazine 321 mg, 2.79 mmol) and sodium carbonate (564 mg, 5.32 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was poured into water (20 mL) and AcOH (6 mL) added. The mixture was extracted with EtOAc (50 mL*4). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude product as pale brown solid. The crude was purified by flash column chromatography over a 4 g silica gel (gradient: DCM: CH3OH from 100:0 to 96:4).The desired fractions were collected, and the solvent was concentrated under vacuum to (ACT6051WOPCT1) give the title compound as a pale brown solid (630 mg, 93.4%). LCMS (ESI): mass calcd. for C9H8BrN5, 266.1; m/z found, 268.1 [M+H]+.1H NMR (400MHz, DMSO-d6) δ = 8.45 (s, 1H), 7.93 (d, J=1.7 Hz, 1H), 7.01 (d, J=1.8 Hz, 1H), 5.86 - 5.81 (s, 2H), 3.91 (s, 3H) Step e, 1-methyl-8-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine
Figure imgf000059_0001
[00334] To a mixture of 8-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-amine (300 mg, 1.13 mmol), pyridin-3-ylboronic acid (152 mg, 1.24 mmol) and 1,1'-bis[di t-butylphosphino)ferrocene]palladium chloride (147 mg, 0.23 mmol) in dioxane (24 mL) and water (6 mL) was added potassium carbonate (467 mg, 3.38 mmol) at room temperature. Then the reaction mixture was purged with N2 for 3 minutes. Then the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The crude was purified by flash column chromatography over a 4 g silica gel (gradient: DCM: CH3OH from 100:0 to 90:10). The desired fractions were collected, and the solvent was concentrated under vacuum to give the title product as a pale brown solid (280 mg, 76.6%). LCMS (ESI): mass calcd. for C14H12N6, 264.3; m/z found, 265.2 [M+H]+. Step f. N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(pyridin-3-yl)- 1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide
Figure imgf000059_0002
[00335] To a mixture of 5-bromo-N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6- methylnicotinamide (280 mg, 0.82 mmol), 1-methyl-8-(pyridin-3-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-amine (245 mg, 0.82 mmol), methanesulfonato(2- dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'- biphenyl-2-yl)palladium(ii) (186 mg, 0.21 mmol) and 2-(dicyclohexylphosphino)-3,6- dimethoxy--2',4',6'-triisopropyl-1,1'-biphenyl (110 mg, 0.21 mmol) in DMF (20 mL) was added cesium carbonate (804 mg, 2.47 mmol) at room temperature. The reaction mixture was purged with N2 for 2 minutes. The reaction mixture was stirred at 100°C for 15 hrs. The (ACT6051WOPCT1) reaction mixture was purified by Prep-HPLC. column: Boston Green ODS 150*30mm*5um; Condition: A: water (0.225%FA), B: MeCN; at the beginning: A (95%) and B (5%), at the end: A (65%) and B (35%); Gradient Time(min) 7; 100%B Hold Time(min) 3; Flow Rate(ml/min) 35. The pure fractions were collected, and the solvent was evaporated under vacuum, lyophilized to dryness to give the title compound (45 mg) as an off-white solid. LCMS (ESI): mass calcd. for C29H33N9O, 523.6; m/z found, 524.4 [M+H]+.1H NMR (400MHz, METHANOL-d4) δ = 8.94 (d, J=1.8 Hz, 1H), 8.73 (d, J=1.9 Hz, 1H), 8.51 (s, 1H), 8.48 (d, J=1.9 Hz, 1H), 8.44 (s, 1H), 8.41 (dd, J=1.3, 4.9 Hz, 1H), 8.23 (d, J=1.7 Hz, 1H), 8.19 (td, J=1.8, 8.0 Hz, 1H), 7.47 (dd, J=4.8, 7.9 Hz, 1H), 7.30 (d, J=1.7 Hz, 1H), 4.19 (s, 3H), 3.78 (t, J=6.3 Hz, 2H), 3.62 (br s, 2H), 3.32 (br s, 2H), 2.67 (s, 3H), 2.20 - 2.10 (m, 2H), 2.08 - 2.00 (m, 2H), 1.41 (s, 6H) Example 2. (S)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(2-methylmorpholino)ethyl)nicotinamide
Figure imgf000060_0001
Step a. (S)-2-(2-methylmorpholino)acetonitrile
Figure imgf000060_0002
[00336] To a solution of (S)-2-methylmorpholine (1 g, 9.89 mmol) and potassium carbonate (3.42 g, 24.72 mmol) in acetonitrile (16 mL) was added 2-bromoacetonitrile (680 µL, 10.94 mmol) at room-temperature. The resulting mixture was stirred at 50 °C for 12 h. The reaction was concentrated under reduced pressure to give crude product, which was purified by column chromatography over silica gel (eluent: ethyl acetate in petroleum ether (0 to 50%)) to give the title compound (S)-2-(2-methylmorpholino) acetonitrile as colorless oil (740 mg, 53.4%).1H NMR (400 MHz, CHLOROFORM-d) δ = 3.95 - 3.89 (m, 1H), 3.73 - 3.60 (m, 2H), 3.52 (s, 2H), 2.71 - 2.57 (m, 2H), 2.55 - 2.47 (m, 1H), 2.23 - 2.15 (m, 1H), 1.19 (d, J = 6.3 Hz, 3H) Step b. (S)-2-(2-methylmorpholino)ethan-1-amine
Figure imgf000060_0003
(ACT6051WOPCT1) [00337] To a solution of (S)-2-(2-methylmorpholino) acetonitrile (500 mg, 3.57 mmol) in THF (10 mL) was added lithium aluminium hydride (162 mg, 4.27 mmol) by portions at 0 °C (ice/water).The mixture was stirred at room temperature for 1 hours before quenched with water (0.2 mL) at 0 °C. The reaction mixture was filtered. And the filtration was concentrated to dryness under reduced pressure to afford the crude product 2-(2, 2- dimethylpyrrolidin-1-yl)ethanamine a yellow oil. Step c.1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-amine
Figure imgf000061_0001
[00338] To the mixture of 8-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-amine (3 g, 11.27 mmol) in 1,4-dioxane/H2O=4:1 (150 mL) was added 1- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.8 g, 13.46 mmol) and Cs2CO3 (11 g, 33.76 mmol), then Pd(dppf)Cl2·CH2Cl2 (1.5 g, 1.84 mmol) was added. The system was degassed by applying alternating N2 atmosphere. The resulting mixture was heated at 100 °C and stirred for 12 hours. The mixture was concentrated under vacuum to give the product as black solid. The black solid was purified by silica gel column chromatography (eluent: DCM/MeOH from 100:0 to 70:30). The fractions were collected and the solvent was removed to give 1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-amine (2.1 g, 7.19 mmol, 63.8%) as brown solid. LCMS (ESI): mass calcd. for C13H13N7267.3; m/z found, 268.2 [M+H]+. Step d.6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinic acid
Figure imgf000061_0002
[00339] To the mixture of 5-bromo-6-Methylnicotinicacid (200 mg, 0.93 mmol) in DMF (10 mL) was added 1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-amine (179 mg, 0.61 mmol) and CsCO3 (983 mg, 3.02 mmol), then Brettphos (100 mg, 0.19 mmol) and Brettphos-Pd-G3 (180 mg, 0.20 mmol) was added. N2 was bubbled into the mixture for 1 min, and the vial was sealed with a rubber septum. (ACT6051WOPCT1) The resulting mixture was heated at 90 °C and stirred for 2 h. The mixture was concentrated under vacuo to give product as back solid. The black solid was purified by silica gel column chromatography (eluent: DCM:MeOH from 100:0 to 90:10). The fractions were collected and the solvent was removed to give the title compound as brown solid (660 mg, 91.8%). LCMS (ESI): mass calcd. for C20H18N8O2402.4; m/z found, 403.2 [M+H]+. Step e. (S)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(2-methylmorpholino)ethyl)nicotinamide N N H O O N N N N N N N H N [00340] To the mixture of 6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)- 1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino) nicotinic acid (100 mg, 0.19 mmol) in DMF (4 mL) was added (S)-2-(2-methylmorpholino) ethylamine (30 mg, 0.21 mmol) and DIEA(128 µL, 0.77 mmol), then HATU (87 mg, 0.229 mmol) was added. The resulted mixture was heated at r.t. and stirred for 2 h, concentrated to dryness in vacuum. The yellow oil was purified by Prep-HPLC. column: Welch Xtimate C18150*30mm*5um, Condition: A: water (FA), B: MeCN; at the beginning: A (94%) and B (6%), at the end: A (64%) and B (36%); Gradient Time(min) 7.7; 100%B Hold Time(min) 2.5; Flow Rate(ml/min) 60. The pure fractions were collected, and the solvent was evaporated under vacuum, lyophilized to dryness to the title compound as a brown solid (19.3 mg, 18.7%). LCMS (ESI): mass calcd. for C27H32N10O2528.6; m/z found, 529.3 [M+H]+.1H NMR (400 MHz, METHANOL- d4) δ = 8.69 - 8.64 (m, 1H), 8.47 (d, J = 1.8 Hz, 1H), 8.45 - 8.42 (m, 1H), 7.96 - 7.89 (m, 2H), 7.83 - 7.77 (m, 1H), 7.06 - 7.00 (m, 1H), 4.20 - 4.10 (m, 3H), 4.02 - 3.96 (m, 1H), 3.96 - 3.91 (m, 3H), 3.80 - 3.64 (m, 4H), 3.32 - 3.22 (m, 2H), 3.01 (br t, J = 6.2 Hz, 2H), 2.72 - 2.61 (m, 4H), 2.41 - 2.31 (m, 1H), 1.19 (s, 3H) [00341] The following tabulated Examples were prepared by a similar method of Example 1 or Example 2 from the appropriate starting materials
Figure imgf000062_0001
(ACT6051WOPCT1)
Figure imgf000063_0001
(ACT6051WOPCT1)
Figure imgf000064_0001
(ACT6051WOPCT1)
Figure imgf000065_0001
(ACT6051WOPCT1)
Figure imgf000066_0001
(ACT6051WOPCT1)
Figure imgf000067_0001
(ACT6051WOPCT1)
Figure imgf000068_0001
(ACT6051WOPCT1)
Figure imgf000069_0001
(ACT6051WOPCT1)
Figure imgf000070_0001
(ACT6051WOPCT1)
Figure imgf000071_0001
(ACT6051WOPCT1)
Figure imgf000072_0001
(ACT6051WOPCT1) Example 53, (S)-N-((1-isopropylpyrrolidin-2-yl)methyl)-6-methyl-5-((1-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)nicotinamide
Figure imgf000073_0001
Step a, tert-butyl (S)-2-((5-bromo-6-methylnicotinamido)methyl)pyrrolidine-1-
Figure imgf000073_0002
[00342] A mixture of 5-bromo-6-methylnicotinic acid (600 mg, 2.78 mmol), DIEA (1.82 mL, 11.01 mmol) in dichloromethane (20 mL) was added HATU (1.56 g, 4.10 mmol) were added a 40 mL thread vial equipped with magnetic stirrer at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then (S)-tert-butyl 2- (aminomethyl)pyrrolidine-1-carboxylate (672 mg, 3.36 mmol) was added. The reaction vessel was stirring for 3 h at r.t. The reaction mixture or solution was concentrated to dryness in vacuum given a yellow oil. The yellow oil was subjected to column chromatography over silica gel (gradient elution: 0 - 20% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuum to give (S)-tert-butyl 2-((5-bromo-6- methylnicotinamido)methyl)pyrrolidine-1-carboxylate as colorless oil. LCMS (ESI): mass calcd. for C17H24BrN3O3398.3; m/z found, 399.2 [M+H]+. Step b. (S)-5-bromo-6-methyl-N-(pyrrolidin-2-ylmethyl)nicotinamide
Figure imgf000073_0003
[00343] A mixture of (S)-tert-butyl 2-((5-bromo-6- methylnicotinamido)methyl)pyrrolidine-1-carboxylate (1.1 g, 2.76 mmol) in DCM (5 mL) was added a 50 mL round-bottomed flask equipped with magnetic stirrer at room temperature under an atmosphere of nitrogen. Then HCl in dioxane (6 mL) was added at r.t. N2 was bubbled into the mixture for 5 min. The reaction vessel was gradually warmed to 25 °C over (ACT6051WOPCT1) the course of 10 min, after which time stirring was continued for 4 h. The reaction mixture was concentrated to dryness in vacuum give (S)-5-bromo-6-methyl-N-(pyrrolidin-2- ylmethyl)nicotinamide as white solid that was used directly for the next step without purification. LCMS (ESI): mass calcd. for C12H16BrN3O 298.2; m/z found, 399.1 [M+H]+. Step c. (S)-5-bromo-N-((1-isopropylpyrrolidin-2-yl)methyl)-6-methylnicotinamide
Figure imgf000074_0001
[00344] A mixture of (S)-5-bromo-6-methyl-N-(pyrrolidin-2-ylmethyl)nicotinamide (200 mg, 0.54 mmol, 2HCl), acetone (200 uL, 2.72 mmol), Na(CN)BH3 (50 mg, 0.80 mmol) and TEA (400 uL, 2.87 mmol) in DCM (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to give the crude product. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH from 100/0 to 15/1). The desired fractions were collected and the solvent was concentrated to dryness under vacuum to give the (S)-5-bromo-N-((1-isopropylpyrrolidin-2-yl)methyl)-6- methylnicotinamide (120 mg, 0.35 mmol) as solid. LCMS (ESI): mass calcd. for C15H22BrN3O 340.3; m/z found, 341.6 [M+H]+. Step d. (S)-N-((1-isopropylpyrrolidin-2-yl)methyl)-6-methyl-5-((1-methyl-8-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide
Figure imgf000074_0002
[00345] A mixture of 1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-amine (150 mg, 0.56 mmol), (S)-5-bromo-N-((1- isopropylpyrrolidin-2-yl)methyl)-6-methylnicotinamide (200 mg, 0.59 mmol), Brettphos-Pd- G3 (75 mg, 0.083 mmol), Brettphos (60 mg, 0.112 mmol) and Cs2CO3 (562.5 mg, 1.73 mmol) in DMF (10 mL) was stirred at 100°C for 1 hour. Water (30 mL) was added and the mixture was extracted with Ethyl acetate (50 mL*3). The combined organic layers were washed with sat.NaCl (20 mL*3) then concentrated under vacuum to give the crude product. The crude product was purified by column on silica gel(eluent: DCM/MeOH =0% to 50%). The pure fractions were collected and the solvent was evaporated to give a yellow oil. The yellow oil was then purified by preparative high-performance liquid chromatography over (ACT6051WOPCT1) Column: Phenomenex C1880*40mm*3um. Condition: A: water(NH3H2O), B: MeCN; at the beginning: A (66%) and B (34%), at the end: A: (36%) and B (64%). Gradient Time (min) 8; 100% B Hold Time(min) 3; Flow Rate(ml/min) 30. The pure fractions were collected and the solvent was evaporated under vacuum, lyophilized to dryness to give the (S)-N-((1-isopropylpyrrolidin-2-yl)methyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol- 4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide (20 mg) as white solid. LCMS (ESI): mass calcd. for C28H34N10O 526.6; m/z found, 527.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 - 1.30 (m, 6 H), 1.68 - 2.05 (m, 4 H), 2.61 (s, 3 H), 2.74 - 3.01 (m, 1 H), 3.43 - 3.63 (m, 4 H), 3.87 (s, 3 H), 4.10 (s, 3 H), 7.16 (d, J=1.25 Hz, 1 H), 7.82 (s, 1 H), 8.04 (s, 1 H), 8.07 (d, J=1.51 Hz, 1 H), 8.33 (s, 1 H), 8.52 (s, 1 H), 8.54 (s, 1 H), 8.58 (s, 1 H), 8.78 (br s, 1 H) [00346] The following tabulated Examples were prepared by a similar method of Example 53 from the appropriate starting materials
Figure imgf000075_0001
(ACT6051WOPCT1)
Figure imgf000076_0001
Biological Assays [00347] PDGFRβ HTRF assay [00348] I. Materials [00349] Reagents
Figure imgf000076_0002
(ACT6051WOPCT1)
Figure imgf000077_0001
[00350] Instrumentation: a. Compound liquid handling: LabCyte Echo; b. Reagent liquid handling: Thermo Scientific Multidrop Combi; c. BMG PHERAStar multilabel plate reader. [00351] Protein Reagent: His6-TEV-PDGFRβ Protein Prep prepared at Accelagen. [00352] II. Methods and Procedures [00353] Stock solutions: (ACT6051WOPCT1) [00354] Assay buffer stock solution, contains 50 mM Hepes, 10 mM MgCl2, 1 mM EGTA, and 0.01% Brij-35, 0.01% ovalbumin, 2 mM DTT at pH 7.5, in molecular biology grade water. Store at room temperature. [00355] DTT, 2 M in molecular biology grade water, store at -20°C in aliquots. [00356] Ovalbumin, 10% or 100 mg/mL, prepare fresh on experimental day. [00357] PDGFRβ, 116 µM (PDGFRb_08 Prep 02), produced at Accelagen. Store at -80°C in aliquots. [00358] TK-biotin peptide, 0.5 µM in molecular biology grade water, store at - 20°C in aliquots. [00359] ATP, 100 mM in molecular biology grade water, store at -20°C in aliquots. [00360] HTRF KinEASE-TK kit: Allow the contents of the Cisbio kit to warm up to room temperature before use. This kit contains HTRF detection buffer, TK-Antibody labeled with Eu3+-cryptate, TK-substrate biotin and Streptavidin-XL665. [00361] TK Substrate-Biotin, reconstitute 500 µg lyopholized with 574 µL molecular biology grade water to prepare a 500 µM stock; After use, aliquot the rest and store at -20°C. [00362] TK Antibody-Cryptate, reconstitute lyophilized with 1 mL of molecular biology grade water (100x solution) then add 99 mL detection buffer to prepare a ready to use TK-antibody-cryptate solution; the concentration of the TK-antibody-cryptate reagent is not known. After use, aliquot the rest and store at -20°C. [00363] Streptavidin-XL665, reconstitute 3 mg lyophilized with 3 mL molecular biology grade water to prepare a 1 mg/mL or 16.67 µM stock; MW = 60 kDa; After use, aliquot the rest and store at -20°C. [00364] Freshly prepared solutions: [00365] Assay buffer. Dilute 5x Kinase buffer 5-fold with molecular biology grade water and add DTT to 2 mM and ovalbumin to 0.1 mg/mL (or 0.01%). [00366] 2X protein solution. Make a working solution of 100 pM PDGFRβ in assay buffer. Keep on ice until use to maintain enzyme stability. [00367] 2X substrate solution. Make a working solution of 1.6 mM ATP and 1 µM TK-substrate biotin peptide in assay buffer. (ACT6051WOPCT1) [00368] 3X quench/detection solution. Make a working solution of 0.1875 µM SA-XL665 and the TK-antibody cryptate diluted by ½ of total quench/detection volume in assay buffer. [00369] Keep final streptavidin/biotin ratio at 1 to 8. [00370] Example of 3x quench/detection solution preparation: 8 mL total volume. [00371] 1x assay buffer – 3910 µL [00372] TK antibody-cryptate in detection buffer – 4000 µL [00373] 0.1875 µM SA-XL665 – 90 uL [00374] The kinase reaction is stopped by the addition of the detection reagents which contain EDTA (detection step). [00375] Assay Procedure: [00376] Assay in white ProxiPlate 384-well [00377] Step 1. Dispensing inhibitors/DMSO and low control: Using the ECHO 555 acoustic dispenser, spot desired compound serial dilutions in DMSO, NEAT DMSO to represent the uninhibited enzyme control, and 10 µM final [imatinib] to the represent the 100% inhibited enzyme control [00378] Step 2. PDGFRβ E + I pre-incubation: Add 2 µL 2x protein solution to columns 1-24 using the Multidrop Combi. Centrifuge at 1000 rpm for 1 min. Incubate 30 min at RT [00379] Step 2. Enzymatic reaction: Add 2 µL substrate solution to columns 1-24 to initiate the reaction using the Multidrop Combi; cover/seal the assay plate to reduce evaporation. Centrifuge at 1000 rpm for 1 min. Incubate at room temperature for 3 hours. [00380] Final concentrations of components in PDGFRβ cascade assay: [00381] 50 mM Hepes, pH 7.5 [00382] 10 mM MgCl2 [00383] 0.01% Brij-35 [00384] 1 mM EGTA [00385] 2 mM DTT [00386] 0.01% Ovalbumin [00387] 50 pM inactive PDGFRβ [00388] 0.5 µM TK-substrate biotin peptide (ACT6051WOPCT1) [00389] 62.5 nM SA-XL-665 [00390] TK antibody-Eu3+-cryptate (diluted by 1/3 final from stock) [00391] 800 µM ATP [00392] ≤ 1% DMSO [00393] Step 3. Quench/Detection: Add 2 µl 3x quench/detection solution to columns 1-24 using the Multidrop Combi; cover/seal the plate. Centrifuge 1 min 1000 rpm. Incubate at RT for 60 min. Read the plate in PHERAstar (or similar instrument) on HTRF setting at excitation 337nm - dual emission - 665/620 nm ratio. [00394] III. Calculations and Formulas [00395] HTRF ratio values calculated by the instrument (Ratio is acceptor counts/donor counts * 10,000) is exported from the plate reader and used in data analysis. The exported data will be used to calculate 1) compound activity and 2) assay statistics. Compound activity is represented by % Inhibition when testing a single dose of a compound or IC50 when testing a dose response of a compound. Assay statistics can include Robust Z’ and Signal to Background. [00396] % Inhibition Calculation: Percent inhibition will be calculated for sample wells based on the equation: ( ^^^^ − ^^^^ ^^^^) % ^^^^ ^^^^ℎ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ =� ( ^^^^ ^^^^ − ^^^^ ^^^^)� ∗ 100) [00397] Where, x: sample activity; cr: central reference is calculated based on wells containing all assay components and no compound (DMSO only); sr: scale reference is calculated based on wells inhibited with 10 µM Imatinib (these wells will contain the enzyme and substrate solutions) [00398] IC50 Calculation: For IC50 determination, full 11- point dose response data will be processed using the following equation:
Figure imgf000080_0001
[00399] Where S0=Activity level at zero concentration of test compound; SInf=Activity level at infinite concentration; IC50: Concentration at which activity reaches 50% of maximum level; c= Concentration in logarithmic units corresponding to the values on the x-axis of the dose-response curve plot; Hill coefficient n= Measure of the slope at IC50. See Table 1, below. (ACT6051WOPCT1) [00400] Registered Parameters (when applicable): % Activity, IC50, nHill Slope, Sinf, S0, and Comments [00401] Robust Z’ Calculation: Robust Z prime (RZ’) value will be calculated as defined by the following equation:
Figure imgf000081_0001
− sr [00402] Where, RSD: Robust standard deviation; cr: central reference is calculated based on wells containing all assay components and no compound (DMSO only); sr: scale reference is calculated based on wells inhibited with 10 µM Imatinib compound (these wells will contain the enzyme and substrate solutions) [00403] Signal to Background, S/B, Calculation [00404] Where, CR, Central Reference (no compound wells); SR, Scale Reference (inhibitor control wells). [00405] PDGFRβ LanthaScreen assay [00406] I. Materials
Figure imgf000081_0002
(ACT6051WOPCT1) [00407] II. Methods and Procedures [00408] Stock solutions: [00409] Assay buffer stock contains 50 mM HEPES pH7.5, 10 mM MgCl2, 0.01% Brij- 35, 1 mM EGTA. [00410] Tb-labeled inactive PDGFRβ.3.6 µM in 50 mM HEPES, pH 7.4, 150 mM NaCl, 0.005% Tween-20 and 10% glycerol. Store at -80 oC in aliquots. [00411] Tracer 222, 50 µM in DMSO, store at -20 oC. [00412] Freshly prepared solutions: [00413] Assay buffer. Add DTT to 2 mM and ovalbumin to 0.1 mg/mL to Assay buffer stock. [00414] Kinase-Tracer solution. Make a working solution of 0.2 nM Tb-labeled inactive PDGFRβ and 40 nM Tracer 222 in Assay buffer. Keep on ice until use. [00415] Assay Procedure: [00416] Step 1. Dispensing inhibitors: Using Echo, dispense 40nL/well (or less) compound serial dilutions in DMSO onto the assay plate. [00417] Step 2. Dispensing Kinase-Tracer solution: Add 4 µL/well Kinase-Tracer solution. Seal the plate with optically transparent plate seal. Centrifuge at 1000 rpm for 1 min. [00418] Final concentrations of components in the assay: [00419] [Tb-PDGFRβ] = 0.2 nM; [00420] [Tracer 222] = 40 nM; [00421] [DMSO] ^ 1%. [00422] Step 3. Detection: Read TR-FRET signals after 18 hours incubation at room temperature. [00423] III. Calculations and Formulas [00424] % Inhibition: % Inhibition = (NC – sample) / (NC – PC) * 100 where NC is the mean of negative control (reactions without inhibitor), and PC is the mean of positive control (1µM sunitinib). [00425] IC50 determination: Compounds are serially diluted 3-fold and tested in an 11- point dose response. IC50 values are determined from a 4-parameter fit, using the following equation: Y = Bottom + (Top – Bottom) / (1+10((Log IC50-X)*Hill slope)), where X = log10 (ACT6051WOPCT1) of the compound concentration; top can be defined by PC; bottom defined by NC. See Table 1, below. [00426] PDGFRβ cellular assay [00427] I. Materials
Figure imgf000083_0001
[00428] II. Methods and Procedures [00429] Cell Culture and Preparation: Cells are cultured according to ATCC procedure (5) with the addition of the antibiotic penicillin-streptomycin. If working from frozen, cells should be thawed according to ATCC procedure. Depending on the cell density of frozen vial, cells will need time to recover from thaw. An 80% confluent T75 flask should be enough for one 384 well plate. [00430] Stock Solutions: Rat PDGFBB. A 100ug/mL stock is prepared by reconstituting 50ug in 500uL of 4mM HCl and 0.1% BSA. It can be stored for a month at 4°C, or aliquoted out and frozen in the -20/-80°C to avoid multiple free-thaw cycles. [00431] Freshly Prepared Solutions: [00432] 1x Cisbio cell lysis buffer. The cell lysis buffer is diluted 4-fold with molecular grade water. The blocking agent is then diluted 25-fold in the diluted lysis buffer. [00433] Antibody solutions. Equal amounts d2 and cryptate antibody are diluted 20-fold in detection buffer. (ACT6051WOPCT1) [00434] Rat PDGFBB. A working stock of 100ng/mL is created from the stock solution in 10%FBS culture media. [00435] Assay Steps [00436] Step 1: Plating Cells: Media from the A10 cell flask is aspirated. The cells are rinsed with PBS and then trypsinized to disperse the cell layer. The cells are then pelleted are resuspended to 1.25e5 cells/mL. 40uL of cells are then plated in 384 Greiner TC treated plates at a density of 5000 cells/well using the Combi. Plates are covered and placed in the incubator (37°C 5% CO2) overnight to allow cells to adhere. [00437] Step 2: Compound Dispense: Approximately 18 hours after plating, dispense 40nL compound onto cells using Echo. Column 12 is the neutral control DMSO, column 24 is the inhibitor control 10 mM Imatinib (10uM final assay concentration). The plate is returned to the incubator for 3 hours. [00438] Step 3: Activation by PDGFbb: 6uL of the working stock of 100ng/mL PDGFbb is dispensed using the Tempest to give a final assay concentration of 15ng/mL (EC80). After 10 minutes the media is removed by flicking the plate. [00439] Step 4: Cell lysis and antibody addition: 20uL lysis buffer per well is added to the plate via Tempest. 5uL antibody solution is added per well via the Tempest. The plate is placed on the shaker at 230 rpm for 1 hour at room temperature. [00440] Step 5: Detection: The plate is read using the HTRF module on the BMG Pherastar. Data is analyzed using Genedata Screener. [00441] III. Calculations and Formulas: [00442] % Inhibition: % Inhibition = (NC – sample) / (NC – PC) * 100 where NC is the mean of negative control (reactions without inhibitor), and PC is the mean of positive control (10µM imatinib). [00443] IC50 determination: Compounds are serially diluted 3-fold and tested in an 11- point dose response. IC50 values are determined from a 4-parameter fit, using the following equation: Y = Bottom + (Top – Bottom) / (1+10((Log IC50-X)*Hill slope)), where X = log10 of the compound concentration; top can be defined by PC; bottom defined by NC. See Table 1, below. [00444] VEGFR ADP GLO assay [00445] I. Materials (ACT6051WOPCT1)
Figure imgf000085_0001
[00446] II. Methods and Procedures [00447] Stock solutions: [00448] Assay buffer stock contains 50mM HEPES pH7.5, 10mM MgCl2, 0.01% Brij-35, and 1mM EGTA. [00449] Unphosphorylated VEGFR2.52.6 µM in 50 mM Tris-HCl, pH 8.0, 50 mM NaCl, 5% Glycerol, 0.5 mM TCEP. Store at -80 oC in aliquots. [00450] 10mg/mL srctide solution, prepared in Assay buffer (Assay buffer stock with 2mM DTT, 0.1% Pluronic F-127, and 0.1mg/mL ovalbumin). Sonicate 10 mg/ml Srctide solution for 10 minutes and then vacuum filter. [00451] Freshly prepared solutions (ACT6051WOPCT1) [00452] Assay buffer. Add DTT to 2mM, Pluronic F-127 to 0.1% and ovalbumin to 0.1mg/mL to Assay buffer stock. [00453] 2X kinase solution. Make a working solution of 10 nM unphosphorylated VEGFR2 in Assay buffer. Vacuum filter 2x kinase solution prior to running assay. Keep on ice until use. [00454] 2X substrate/ATP solution. Make a working solution of 2mg/mL srctide and 2.4mM ATP in Assay buffer. Keep on ice until use. [00455] Assay Procedure: [00456] Step 1. Dispensing inhibitors/controls: Using Echo, dispense 10nL/well compound serial dilutions in DMSO to columns 1-22 (in 384-well plates) or columns 1-44 (in 1536-well plates). Dilution series = 11 pt, 3-fold dilutions. The top compound concentration in the source plate is 4 mM. The top compound concentration in the assay plate is 10 uM. Using Echo, dispense 10 nl/well DMSO to column 23 (in 384-well plates) or columns 45-47 (in 1536-well plates). These wells will serve as negative control wells Using Echo, dispense 10 nl/well 400 uM TAK-593 in DMSO to column 24 (in 384-well plates) or column 48 (in 1536-well plates). The final concentration of TAK-593 in the assay should be 1 uM. These wells will serve as positive control wells. [00457] Step 2. Pre-incubation of inhibitors with kinase: Add 2 µL/well 2X kinase solution. Centrifuge at 1000 rpm for 1 min. Incubate at room temperature for 30 min. [00458] Step 3. Kinase cascade reaction: Add 2 µL/well 2X substrate/ATP solution to initiate kinase reactions. Centrifuge at 1000 rpm for 1 min. Incubate at room temperature for 180 min. [00459] Final concentrations of components in the assay: [00460] [VEGFR2] = 5 nM; [00461] [ATP] = 1.2 mM; [00462] [Srctide] = 1 mg/mL; [00463] [DMSO] ^ 1%. [00464] Step 4. Quench: Add 2 uL/well ADP Glo Reagent + 0.05% CHAPS. Centrifuge at 1000 rpm for 1 min; Incubate at room temperature for one hour. [00465] Step 5. Detection: Add 2uL/well Kinase Detection Reagent + 0.05% CHAPS. Centrifuge at 1000 rpm for 1 min; Incubate at room temperature for 1 hour; Read Luminescence on a plate reader. (ACT6051WOPCT1) [00466] III. Calculations and Formulas [00467] % Inhibition: % Inhibition = (NC – sample) / (NC – PC) * 100 where NC is the mean of negative control (reactions without inhibitor), and PC is the mean of positive control (1µM TAK-593). [00468] IC50 determination: Compounds are serially diluted 3-fold and tested in an 11- point dose response. IC50 values are determined from a 4-parameter fit, using the following equation: Y = Bottom + (Top – Bottom) / (1+10(Log IC50-X)*Hill slope), where X = log10 of the compound concentration; top can be defined by PC; bottom defined by NC. See Table 1, below. Table 1. Biology chemical and cellular activity
Figure imgf000087_0001
ĨACT6051WOPCT1)
Figure imgf000088_0001

Claims

103693.005210 (ACT6051WOPCT1) What is claimed: 1. A compound of formula (I):
Figure imgf000089_0001
or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted phenyl ring or an optionally substituted pyridinyl ring; R1 is optionally substituted C1-C6alkyl or optionally substituted C3-C5cycloalkyl; R2 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted C1-C6-alkyl-cycloalkyl, optionally substituted C1-C6-alkyl, or optionally substituted heterocycloalkyl; n is 1, 2, or 3; R3 and R4 are each independently optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted spirocycloalkyl, or optionally substituted heterocycloalkyl; or one of R3 or R4 may be H; or R3 and R4 , together with the nitrogen atom to which they are both attached, form an optionally substituted 3-12-membered heterocycloalkyl ring, an optionally substituted 5- 12-membered bridged heterocycloalkyl ring, an optionally substituted 4- 12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12- membered spiroheterocycloalkyl ring system, wherein said 3-12-membered heterocycloalkyl ring, 5-12- membered bridged heterocycloalkyl ring, 4-12-membered fused heterocycloalkyl ring (ACT6051WOPCT1) system, or 5-12-membered spiroheterocycloalkyl ring system may include, in addition to the nitrogen atom to which both R3 and R4 are attached, 1-3 other heteroatoms that are each independently O, S, or N; each R5 and each R6 is independently H, C1-C6alkyl, or C3-C5cycloalkyl; or an R5 and R6 attached to the same carbon atom, together with that carbon atom, may form a C3-C6cycloalkyl ring; or an R5 or R6, together with an R3 or R4 may form an optionally substituted 3- 12- membered heterocycloalkyl ring, an optionally substituted 5-12-membered bridged heterocycloalkyl ring, an optionally substituted 4-12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12-membered spiroheterocycloalkyl ring system; and L is -C(O)NH-, -NHC(O)-, or -NHC(O)NH, wherein when n is 1, L is -NHC(O)-. 2. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (IA):
Figure imgf000090_0001
or a pharmaceutically acceptable salt thereof, wherein Q is N or CH; R7 is H, C1-C6alkyl, C3-C6cycloalkyl, halogen, -CN, or C1-C4fluoroalkyl; and R8 is H, C1-C6alkyl, C3-C6cycloalkyl, halogen, or C1-C4fluoroalkyl. 3. The compound according to claim 2, wherein Q is N. (ACT6051WOPCT1) 4. The compound according to claim 2, wherein Q is CH. 5. The compound according to any one of claims 2-4, wherein R7 is C1-C6alkyl. 6. The compound according to any one of claims 2-5, wherein R8 is H. 7. The compound according to claim 2, wherein the compound of formula IA is a compound of formula IA-1:
Figure imgf000091_0001
8. The compound according to claim 2, wherein the compound of formula IA is a compound of formula IA-2:
Figure imgf000091_0002
wherein R7 is -CH3 or -F. 9. The compound according to any one of claims 1-8, wherein R2 is unsubstituted heteroaryl. 10. The compound according to claim 9, wherein the heteroaryl is pyrazinyl, pyrimidinyl, oxazolyl, or pyridinyl. (ACT6051WOPCT1) 11. The compound according to claim 10, wherein the heteroaryl is pyrazinyl. 12. The compound according to claim 10, wherein the heteroaryl is pyrimidin-5-yl or pyrimidin-4-yl. 13. The compound according to claim 10, wherein the heteroaryl is oxazol-5-yl. 14. The compound according to claim 10, wherein the heteroaryl is pyridin-2-yl, pyridin- 3-yl, or pyridin-4-yl. 15. The compound according to any one of claims 1-8, wherein R2 is substituted heteroaryl. 16. The compound according to claim 15, wherein the substituted heteroaryl is substituted pyrazolyl, substituted imidazolyl, substituted triazolyl, substituted furanyl, substituted thiophenyl, substituted pyrimidinyl, or substituted pyridinyl. 17. The compound according to claim 16, wherein the substituted heteroaryl is substituted pyrazolyl. 18. The compound according to claim 17, wherein the substituted pyrazolyl is 1- methylpyrazol-5-yl, 1-methylpyrazol-4-yl, 1,3-dimethylpyrazol-4-yl, 1- cyclopropylpyrazol-4-yl, 1-(2-methoxyethyl)-pyrazol-4-yl, 1-(2-hydroxyethyl)- pyrazol-4-yl, 5-(hydroxymethyl)-1-methylpyrazol-3-yl, 1-(2,3-dihydroxypropan-1- yl)-pyrazol-4-yl, 1-(acetamid-2-yl)-pyrazol-4-yl, 1-(oxetan-3-yl)-pyrazol-4-yl. 19. The compound according to claim 16, wherein the substituted heteroaryl is substituted imidazolyl. 20. The compound according to claim 19, wherein the substituted imidazolyl is 1- methylimidazol-4-yl, or 5-(hydroxymethyl)-1-methylimidazol-2-yl. 21. The compound according to claim 16, wherein the substituted heteroaryl is substituted triazolyl. (ACT6051WOPCT1) 22. The compound according to claim 21, wherein the substituted triazolyl is 1-methyl- 1,2,3-triazol-4-yl. 23. The compound according to claim 16, wherein the substituted heteroaryl is substituted furanyl. 24. The compound according to claim 23, wherein the substituted furanyl is 2- (hydroxymethyl)furan-5-yl. 25. The compound according to claim 16, wherein the substituted heteroaryl is substituted thiophenyl. 26. The compound according to claim 25, wherein the substituted thiophenyl is 2- (hydroxymethyl)thiophen-5-yl. 27. The compound according to claim 16, wherein the substituted heteroaryl is substituted pyridinyl. 28. The compound according to claim 27, wherein the substituted pyridinyl is 2- (hydroxymethyl)pyridin-4-yl. 29. The compound according to claim 16, wherein the substituted heteroaryl is substituted pyrimidinyl. 30. The compound according to any one of the preceding claims, wherein L is -NHC(O)-. 31. The compound according to any one of claims 1-29, wherein L is -C(O)NH-. 32. The compound according to any one of claims 1-29, wherein L is -NHC(O)NH-. 33. The compound according to any one of claims 1-30, wherein n=1. 34. The compound according to any one of claims 1-32, wherein n=2. (ACT6051WOPCT1) 35. The compound according to any one of claims 1-32, wherein n=3. 36. The compound according to any one of the preceding claims, wherein R5 and R6 are each H. 37. The compound according to any one of the preceding claims, wherein R3 is optionally substituted C1-C6alkyl and R4 is optionally substituted heterocycloalkyl. 38. The compound according to any one of claims 1-36, wherein R3 and R4, together with the nitrogen atom to which they are both attached, form an optionally substituted 3- 12-membered heterocycloalkyl ring. 39. The compound according to claim 38, wherein the optionally substituted 3-12- membered heterocycloalkyl ring
Figure imgf000094_0001
Figure imgf000094_0002
40. The compound according to any one of claims 1-36, wherein R3 and R4, together with the nitrogen atom to which they are both attached, form an optionally substituted 5- 12-membered bridged heterocycloalkyl ring. 41. The compound according to claim 40, wherein the optionally substituted 5-12- membered bridged heterocycloalkyl ring
Figure imgf000094_0003
(ACT6051WOPCT1) 42. The compound according to any one of claims 1-36, wherein R3 and R4, together with the nitrogen atom to which they are both attached, form an optionally substituted 5- 12-membered spiroheterocycloalkyl ring. 43. The compound according to claim 42, wherein the optionally substituted 5-12- membered spiroheterocycloalkyl ring
Figure imgf000095_0001
44. The compound according to any one of claims 1-36, wherein R3 and R4, together with the nitrogen atom to which they are both attached, form an optionally substituted 4- 12-membered fused heterocycloalkyl ring system. 45. The compound according to claim 44, wherein the optionally substituted 4-12- membered fused heterocycloalkyl ring system
Figure imgf000095_0002
46. The compound according to any one of claims 1-36, wherein an R3 or R4, together with an R5 or R6 form an optionally substituted 3- 12-membered heterocycloalkyl ring, an optionally substituted 5-12-membered bridged heterocycloalkyl ring, an optionally substituted 4-12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12-membered spiroheterocycloalkyl ring system. 47. The compound according to claim 46, wherein an R3 or R4, together with an R5 or R6 form an optionally substituted 3- 12-membered heterocycloalkyl ring. 48. The compound according to claim 1 or claim 7, or a pharmaceutically acceptable salt thereof, wherein the compound is: N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(pyridin-3-yl)-1H- pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; (ACT6051WOPCT1) (S)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(2- methylmorpholino)ethyl)nicotinamide; N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; 6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-(pyrrolidin-1-yl)ethyl)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(2-methylpyrrolidin-1- yl)ethyl)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-(2-methylpyrrolidin-1-yl)ethyl)nicotinamide; N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(pyridin-4-yl)-1H- pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; 6-methyl-5-((1-methyl-8-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)-N-(2-(pyrrolidin-1-yl)ethyl)nicotinamide; rac-N-(2-((2R,6R)-2,6-dimethylmorpholino)ethyl)-6-methyl-5-((1-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)nicotinamide; N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-5-((8-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)- 1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-6- methylnicotinamide; rac-N-(2-((2R,6R)-2,6-dimethylmorpholino)ethyl)-6-methyl-5-((1-methyl-8-(pyridin- 3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; 5-((8-(1-(2-amino-2-oxoethyl)-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6- methylnicotinamide; (ACT6051WOPCT1) 5-((8-(1-(2,3-dihydroxypropyl)-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6- methylnicotinamide; N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- imidazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; 6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-morpholinoethyl)nicotinamide; N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(pyrimidin-4-yl)- 1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; N-(2-((3R,5R)-3,5-dimethylmorpholino)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)nicotinamide; 6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)- yl)ethyl)nicotinamide; 6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-(piperidin-1-yl)ethyl)nicotinamide; N-(2-(5-azaspiro[2.4]heptan-5-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; N-(2-(3,3-dimethylazetidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; N-(2-(2,2-dimethylmorpholino)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-5-((8-(5-(hydroxymethyl)-1-methyl-1H- pyrazol-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-6- methylnicotinamide; 6-methyl-N-(2-(methyl(tetrahydro-2H-pyran-4-yl)amino)ethyl)-5-((1-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)nicotinamide; (ACT6051WOPCT1) (S)-5-((8-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-6-methyl-N-(2-(2-methylpyrrolidin-1- yl)ethyl)nicotinamide; (S)-5-((8-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-6-methyl-N-(2-(2-methylpyrrolidin-1- yl)ethyl)nicotinamide; (R)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(2-methylpyrrolidin-1- yl)ethyl)nicotinamide; N-(2-(4-methoxypiperidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; N-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)nicotinamide; N-(2-(8-oxa-5-azaspiro[3.5]nonan-5-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(2-methylpyrrolidin-1- yl)ethyl)nicotinamide; N-(2-(2-oxa-5-azaspiro[3.4]octan-5-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; (S)-5-((8-(5-(hydroxymethyl)thiophen-2-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-6-methyl-N-(2-(2-methylpyrrolidin-1-yl)ethyl)nicotinamide; (S)-5-((8-(5-(hydroxymethyl)furan-2-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-6-methyl-N-(2-(2-methylpyrrolidin-1-yl)ethyl)nicotinamide; (R)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(3-methylpyrrolidin-1- yl)ethyl)nicotinamide; (ACT6051WOPCT1) (S)-5-((8-(2-(hydroxymethyl)pyridin-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-6-methyl-N-(2-(2-methylpyrrolidin-1-yl)ethyl)nicotinamide; (R)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(3- methylmorpholino)ethyl)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-(2-methylpyrrolidin-1-yl)ethyl)nicotinamide; N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-5-((8-(2-(hydroxymethyl)pyridin-4-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-6- methylnicotinamide; N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- 1,2,3-triazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)nicotinamide; N-(2-(2-ethylmorpholino)ethyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4- yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-(3-methylpyrrolidin-1- yl)ethyl)nicotinamide; 6-methyl-5-((1-methyl-8-(pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)-N-(2-morpholinoethyl)nicotinamide; 6-methyl-5-((1-methyl-8-(1-methyl-1H-imidazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-(2-morpholinoethyl)nicotinamide; 6-methyl-5-((1-methyl-8-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3- yl)amino)-N-(2-morpholinoethyl)nicotinamide; (S)-5-((8-(5-(hydroxymethyl)-1-methyl-1H-imidazol-2-yl)-1-methyl-1H- pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-6-methyl-N-(2-(2- methylpyrrolidin-1-yl)ethyl)nicotinamide; 5-((8-(1-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-6-methyl-N-(2-morpholinoethyl)nicotinamide; (ACT6051WOPCT1) 5-((8-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-6-methyl-N-(2-morpholinoethyl)nicotinamide; 5-((8-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-6-methyl-N-(2-morpholinoethyl)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-(2-methylpyrrolidin-1-yl)ethyl)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(pyrazin-2-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-(2-methylpyrrolidin-1-yl)ethyl)nicotinamide; 6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2- b]pyridazin-3-yl)amino)-N-(2-morpholinoethyl)nicotinamide; (S)-N-((1-isopropylpyrrolidin-2-yl)methyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide; (R)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-((1-methylazetidin-2- yl)methyl)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-((1-methylazetidin-2- yl)methyl)nicotinamide; (S)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-((1-methylpyrrolidin-2- yl)methyl)nicotinamide; (R)-6-methyl-5-((1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrrolo[1,2-b]pyridazin-3-yl)amino)-N-((1-methylpyrrolidin-2- yl)methyl)nicotinamide; or (R)-N-((1-isopropylpyrrolidin-2-yl)methyl)-6-methyl-5-((1-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)nicotinamide. 49. A pharmaceutical composition comprising a compound according to any one of claims 1-48, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (ACT6051WOPCT1) 50. A method of treating a disease or disorder in which PDGFR signaling is implicated in a subject in need thereof, comprising administering to said subject an amount of a compound according to any one of claims 1-48, or a pharmaceutically acceptable salt thereof, that is effective to treat said disease or disorder. 51. The method according to claim 50, wherein said disease or disorder is pulmonary hypertension (PH). 52. The method according to claim 51, wherein said pulmonary hypertension is pulmonary arterial hypertension (PAH); PH secondary to heart failure; PH secondary to lung diseases and/or hypoxia; PH due to pulmonary artery obstruction; or PH due to unknown or rare diseases. 53. The method according to claim 52, wherein said pulmonary hypertension is pulmonary arterial hypertension (PAH). 54. A compound according to any one of claims 1-48, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in which PDGFR signaling is implicated in a subject in need thereof. 55. The compound according to claim 54, wherein said disease or disorder is pulmonary hypertension (PH). 56. The compound according to claim 55, wherein said pulmonary hypertension is pulmonary arterial hypertension (PAH); PH secondary to heart failure; PH secondary to lung diseases and/or hypoxia; PH due to pulmonary artery obstruction; or PH due to unknown or rare diseases. 57. The compound according to claim 56, wherein said pulmonary hypertension is pulmonary arterial hypertension (PAH). (ACT6051WOPCT1) 58. Use of a compound according to any one of claims 1-48, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder in which PDGFR signaling is implicated in a subject in need thereof. 59. The use according to claim 58, wherein said disease or disorder is pulmonary hypertension (PH). 60. The use according to claim 59, wherein said pulmonary hypertension is pulmonary arterial hypertension (PAH); PH secondary to heart failure; PH secondary to lung diseases and/or hypoxia; PH due to pulmonary artery obstruction; or PH due to unknown or rare diseases. 61. The use according to claim 60, wherein said pulmonary hypertension is pulmonary arterial hypertension (PAH).
PCT/EP2023/081630 2022-11-14 2023-11-13 Pyrazolopyrrolopyridazines and their uses as pdgfr inhibitors WO2024104968A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263425024P 2022-11-14 2022-11-14
US63/425,024 2022-11-14

Publications (1)

Publication Number Publication Date
WO2024104968A1 true WO2024104968A1 (en) 2024-05-23

Family

ID=88833536

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/081630 WO2024104968A1 (en) 2022-11-14 2023-11-13 Pyrazolopyrrolopyridazines and their uses as pdgfr inhibitors

Country Status (1)

Country Link
WO (1) WO2024104968A1 (en)

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3657744A (en) 1970-05-08 1972-04-25 Univ Minnesota Method for fixing prosthetic implants in a living body
US4739762A (en) 1985-11-07 1988-04-26 Expandable Grafts Partnership Expandable intraluminal graft, and method and apparatus for implanting an expandable intraluminal graft
US4992445A (en) 1987-06-12 1991-02-12 American Cyanamid Co. Transdermal delivery of pharmaceuticals
US5001139A (en) 1987-06-12 1991-03-19 American Cyanamid Company Enchancers for the transdermal flux of nivadipine
US5023252A (en) 1985-12-04 1991-06-11 Conrex Pharmaceutical Corporation Transdermal and trans-membrane delivery of drugs
US5040548A (en) 1989-06-01 1991-08-20 Yock Paul G Angioplasty mehtod
US5061273A (en) 1989-06-01 1991-10-29 Yock Paul G Angioplasty apparatus facilitating rapid exchanges
US5195984A (en) 1988-10-04 1993-03-23 Expandable Grafts Partnership Expandable intraluminal graft
US5292331A (en) 1989-08-24 1994-03-08 Applied Vascular Engineering, Inc. Endovascular support device
US5451233A (en) 1986-04-15 1995-09-19 Yock; Paul G. Angioplasty apparatus facilitating rapid exchanges
US5496346A (en) 1987-01-06 1996-03-05 Advanced Cardiovascular Systems, Inc. Reinforced balloon dilatation catheter with slitted exchange sleeve and method
US5674278A (en) 1989-08-24 1997-10-07 Arterial Vascular Engineering, Inc. Endovascular support device
US6344053B1 (en) 1993-12-22 2002-02-05 Medtronic Ave, Inc. Endovascular support device and method
WO2008112695A2 (en) * 2007-03-12 2008-09-18 Irm Llc Pyrazolo [3,4-d] pyrimidines and 1, 2, 5, 6-tetraaza- as- indacenes as protein kinase inhibitors for cancer treatment
WO2013030802A1 (en) 2011-09-01 2013-03-07 Novartis Ag Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension
WO2021011727A1 (en) * 2019-07-18 2021-01-21 Bristol-Myers Squibb Company PYRAZOLO[3,4-d]PYRROLO[1,2-b]PYRIDAZINYL COMPOUNDS USEFUL AS IRAK4 INHIBITORS
WO2022136509A1 (en) * 2020-12-23 2022-06-30 Actelion Pharmaceuticals Ltd Pyrazolothiazole carboxamides and their uses as pdgfr inhibitors

Patent Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3657744A (en) 1970-05-08 1972-04-25 Univ Minnesota Method for fixing prosthetic implants in a living body
US4739762A (en) 1985-11-07 1988-04-26 Expandable Grafts Partnership Expandable intraluminal graft, and method and apparatus for implanting an expandable intraluminal graft
US4739762B1 (en) 1985-11-07 1998-10-27 Expandable Grafts Partnership Expandable intraluminal graft and method and apparatus for implanting an expandable intraluminal graft
US5023252A (en) 1985-12-04 1991-06-11 Conrex Pharmaceutical Corporation Transdermal and trans-membrane delivery of drugs
US5451233A (en) 1986-04-15 1995-09-19 Yock; Paul G. Angioplasty apparatus facilitating rapid exchanges
US5496346A (en) 1987-01-06 1996-03-05 Advanced Cardiovascular Systems, Inc. Reinforced balloon dilatation catheter with slitted exchange sleeve and method
US4992445A (en) 1987-06-12 1991-02-12 American Cyanamid Co. Transdermal delivery of pharmaceuticals
US5001139A (en) 1987-06-12 1991-03-19 American Cyanamid Company Enchancers for the transdermal flux of nivadipine
US5195984A (en) 1988-10-04 1993-03-23 Expandable Grafts Partnership Expandable intraluminal graft
US5061273A (en) 1989-06-01 1991-10-29 Yock Paul G Angioplasty apparatus facilitating rapid exchanges
US5040548A (en) 1989-06-01 1991-08-20 Yock Paul G Angioplasty mehtod
US5292331A (en) 1989-08-24 1994-03-08 Applied Vascular Engineering, Inc. Endovascular support device
US5674278A (en) 1989-08-24 1997-10-07 Arterial Vascular Engineering, Inc. Endovascular support device
US5879382A (en) 1989-08-24 1999-03-09 Boneau; Michael D. Endovascular support device and method
US6344053B1 (en) 1993-12-22 2002-02-05 Medtronic Ave, Inc. Endovascular support device and method
WO2008112695A2 (en) * 2007-03-12 2008-09-18 Irm Llc Pyrazolo [3,4-d] pyrimidines and 1, 2, 5, 6-tetraaza- as- indacenes as protein kinase inhibitors for cancer treatment
WO2013030802A1 (en) 2011-09-01 2013-03-07 Novartis Ag Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension
WO2021011727A1 (en) * 2019-07-18 2021-01-21 Bristol-Myers Squibb Company PYRAZOLO[3,4-d]PYRROLO[1,2-b]PYRIDAZINYL COMPOUNDS USEFUL AS IRAK4 INHIBITORS
WO2022136509A1 (en) * 2020-12-23 2022-06-30 Actelion Pharmaceuticals Ltd Pyrazolothiazole carboxamides and their uses as pdgfr inhibitors

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"Handbook of Clinical Drug Data", 2002, MCGRAW-HILL
"Principles of Drug Action", 1990, CHURCHILL LIVINGSTON
"Remingtons Pharmaceutical Sciences", 2000, LIPPINCOTT WILLIAMS & WILKINS.
"The Pharmacological Basis of Therapeutics", 2001, MCGRAW HILL, pages: 20037
MARTINDALE: "The Extra Pharmacopoeia", 1999, THE PHARMACEUTICAL PRESS

Similar Documents

Publication Publication Date Title
US11370798B2 (en) Compounds useful as inhibitors of ATR kinase
RU2638116C2 (en) Pyrazolo [3,4-c] pyridines and methods of application thereof
RU2665462C2 (en) 5-azaindazole compounds and methods for use thereof
US12071428B2 (en) Indazole compounds as kinase inhibitors
EP2718293B1 (en) Substituted pyridopyrazines as novel syk inhibitors
KR20210137134A (en) Heteroaromatic and Heterobicyclic Aromatic Derivatives for Treatment of Peroptosis-Related Disorders
KR20220079851A (en) CDK inhibitors and their use as medicaments
EP4267585A1 (en) Pyrazolothiazole carboxamides and their uses as pdgfr inhibitors
EP4289428A1 (en) Nitrogen-containing polycyclic fused ring compound, pharmaceutical composition thereof, preparation method therefor, and use thereof
TW202421130A (en) Isoquinolones as pi3k inhibitors
WO2024104968A1 (en) Pyrazolopyrrolopyridazines and their uses as pdgfr inhibitors
WO2023247596A1 (en) Pyrazolothiazole carboxamides and their uses as pdgfr inhibitors
WO2023007009A1 (en) Pyrazolopyrimidines and their uses as pdgfr inhibitors
WO2023247593A1 (en) Pyrrolopyridine carboxamides and their uses as pdgfr inhibitors
WO2023247595A1 (en) Pyrazolopyrazine carboxamides and their uses as pdgfr inhibitors
WO2023247590A1 (en) Triazolopyridine and benzoisoxazole carboxamides and their uses as pdgfr inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23805947

Country of ref document: EP

Kind code of ref document: A1